Controlling the uniformity of pecvd deposition

ABSTRACT

A method and apparatus for plasma modifying a workpiece such as a syringe barrel, cartridge barrel, vial, or blood tube is described. Plasma is provided within the lumen of the workpiece. The plasma is provided under conditions effective for plasma modification of a surface of the workpiece. A magnetic field is provided in at least a portion of the lumen. The magnetic field has an orientation and field strength effective to improve the uniformity of plasma modification of the interior surface of the generally cylindrical wall. A vessel made according to the process or using the apparatus described above. A pharmaceutical package comprising the syringe barrel or vial containing a pharmaceutical preparation, secured with a closure.

This application is continuation of U.S. application Ser. No. 14/085,749, filed Nov. 20, 2013, which claims priority to the following U.S. Provisional Patent Application Ser. No. 61/800,660, filed Mar. 15, 2013; Ser. No. 61/747,584, filed Dec. 31, 2012; Ser. No. 61/732,180, filed Nov. 30, 2012. These applications are all incorporated here by reference in their entirety to provide continuity of disclosure.

patent application Ser. No. 12/779,007, filed May 12, 2010, now U.S. Pat. No. 7,985,188; PCT/US11/36097, filed May 11, 2011; PCT/US12/64489, filed Nov. 9, 2012; 61/558,885, filed Nov. 11, 2011; 61/636,377, filed Apr. 20, 2012; 61/645,003, filed May 9, 2012; 61/713,435, filed Oct. 12, 2012; 61/716,381, filed Oct. 19, 2012; and 61/732,180, filed Nov. 30, 2012, are all incorporated here by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the technical field of coated surfaces, for example interior surfaces of pharmaceutical packages or other vessels for storing or other contact with fluids. Examples of suitable fluids include foods or biologically active compounds or body fluids, for example blood. The present invention also relates to a pharmaceutical package or other vessel and to a method for coating an inner or interior surface of a pharmaceutical package or other vessel. The present invention also relates more generally to medical devices, including devices other than packages or vessels, for example catheters.

The present disclosure also relates to improved methods for processing pharmaceutical packages or other vessels, for example multiple identical pharmaceutical packages or other vessels used for pharmaceutical preparation storage and delivery, sample collection tubes (e.g. blood collection tubes for venipuncture) and other medical sample collection, and other purposes. Such pharmaceutical packages or other vessels are used in large numbers for these purposes, and must be relatively economical to manufacture and yet highly reliable in storage and use.

BACKGROUND OF THE INVENTION

One important consideration in manufacturing pharmaceutical packages or other vessels for storing or other contact with fluids, for example vials and pre-filled syringes, is that the contents of the pharmaceutical package or other vessel desirably will have a substantial shelf life. During this shelf life, it can be important to isolate the material filling the pharmaceutical package or other vessel from the external environment as well as the vessel wall containing it, or from barrier coatings or layers or other functional layers applied to the pharmaceutical package or other vessel wall to avoid leaching material from the pharmaceutical package or other vessel wall, barrier coating or layer, or other functional layers into the prefilled contents or vice versa.

Since many of these pharmaceutical packages or other vessels are inexpensive and used in large quantities, for certain applications it will be useful to reliably obtain the necessary shelf life without increasing the manufacturing cost to a prohibitive level.

For decades, most parenteral therapeutics have been delivered to end users in Type I medical grade borosilicate glass vessels such as vials or pre-filled syringes. The relatively strong, impermeable and inert surface of borosilicate glass has performed adequately for most drug products. However, the recent advent of costly, complex and sensitive biologics as well as such advanced delivery systems as auto injectors has exposed the physical and chemical shortcomings of glass pharmaceutical packages or other vessels, including possible contamination from metals, flaking, delamination, and breakage, among other problems. Moreover, glass contains several components which can leach out during storage and cause damage to the stored material.

In more detail, borosilicate pharmaceutical packages or other vessels exhibit a number of drawbacks.

Glass is manufactured from sand containing a heterogeneous mixture of many elements (silicon, oxygen, boron, aluminum, sodium, calcium) with trace levels of other alkali and earth metals. Type I borosilicate glass consists of approximately 76% SiO₂, 10.5% B₂O₃, 5% A₁₂O₃, 7% Na₂O and 1.5% CaO and often contains trace metals such as iron, magnesium, zinc, copper and others. The heterogeneous nature of borosilicate glass creates a non-uniform surface chemistry at the molecular level. Glass forming processes used to create glass vessels expose some portions of the vessels to temperatures as great as 1200° C. Under such high temperatures alkali ions migrate to the local surface and form oxides. The presence of ions extracted from borosilicate glass devices may be involved in degradation, aggregation and denaturation of some biologics. Many proteins and other biologics must be lyophilized (freeze dried), because they are not sufficiently stable in solution in glass vials or syringes.

In glass syringes, silicone oil is typically used as a lubricant to allow the plunger tip, piston, stopper, or seal to slide in the barrel. Silicone oil has been implicated in the precipitation of protein solutions such as insulin and some other biologics. Additionally, the silicone oil coating or layer is often non-uniform, resulting in syringe failures in the market.

Glass pharmaceutical packages or other vessels are prone to breakage or degradation during manufacture, filling operations, shipping and use, which means that glass particulates may enter the drug. The presence of glass particles has led to many FDA Warning Letters and to product recalls.

Glass-forming processes do not yield the tight dimensional tolerances required for some of the newer auto-injectors and delivery systems.

As a result, some companies have turned to plastic pharmaceutical packages or other vessels, which provide tighter dimensional tolerances and less breakage than glass.

Although plastic is superior to glass with respect to breakage, dimensional tolerances and surface uniformity, its use for primary pharmaceutical packaging remains limited due to the following shortcomings:

Gas (oxygen) permeability: Plastic allows small molecule gases to permeate into (or out of) the device. The permeability of plastics to gases can be significantly greater than that of glass and, in many cases (as with oxygen-sensitive drugs such as epinephrine), plastics previously have been unacceptable for that reason.

Water vapor transmission: Plastics allow water vapor to pass through devices to a greater degree than glass. This can be detrimental to the shelf life of a solid (lyophilized) drug. Alternatively, a liquid product may lose water in an arid environment.

Leachables and extractables: Plastic pharmaceutical packages or other vessels contain organic compounds that can leach out or be extracted into the drug product. These compounds can contaminate the drug and/or negatively impact the drug's stability.

Clearly, while plastic and glass pharmaceutical packages or other vessels each offer certain advantages in pharmaceutical primary packaging, neither is optimal for all drugs, biologics or other therapeutics. Thus, there can be a desire for plastic pharmaceutical packages or other vessels, in particular plastic syringes, with gas and solute barrier properties which approach the properties of glass. Moreover, there can be a need for plastic syringes with sufficient lubricity and/or passivation or protective properties and a lubricity and/or passivation layer or pH protective coating which can be compatible with the syringe contents. There also can be a need for glass vessels with surfaces that do not tend to delaminate or dissolve or leach constituents when in contact with the vessel contents.

There are additional considerations to be taken into account when manufacturing a prefilled syringe. Prefilled syringes are commonly prepared and sold so the syringe does not need to be filled before use, and can be disposed of after use. The syringe can be prefilled with saline solution, a dye for injection, or a pharmaceutically active preparation, for some examples.

Commonly, the prefilled syringe can be capped at the distal end, as with a cap (or, if the hypodermic needle is preinstalled, a needle shield that can also be a cap), and can be closed at the proximal end by its drawn plunger tip, piston, stopper, or seal. The prefilled syringe can be wrapped in a sterile package before use. To use the prefilled syringe, the packaging and cap are removed, optionally a hypodermic needle or another delivery conduit can be attached to the distal end of the barrel, the delivery conduit or syringe can be moved to a use position (such as by inserting the hypodermic needle into a patient's blood vessel or into apparatus to be rinsed with the contents of the syringe), and the plunger tip, piston, stopper, or seal can be advanced in the barrel to inject the contents of the barrel.

An important consideration regarding medical syringes can be to ensure that the plunger tip, piston, stopper, or seal can move at a constant speed and with a constant force when it is pressed into the barrel. A similar consideration applies to vessels such as pharmaceutical vials which have to be closed by a stopper, and to the stopper itself, and more generally to any surface which is to provide smooth operation of moving parts and/or be passivated or protectively coated.

A non-exhaustive list of documents of possible relevance includes U.S. Pat. Nos. 5,824,198; 5,616,369; 5,468,520; and 5,364,666; and European Patent 0 375 778 B1. These documents are all incorporated by reference.

SUMMARY OF THE INVENTION

An aspect of the invention is a method of plasma modifying a workpiece, for example a syringe barrel or cartridge barrel, having a surface to be treated. “Plasma” in this sense refers to an energized state of matter similar to gas in which a certain portion of the particles of matter are ionized. To carry out the method, plasma is provided in or near the surface under conditions effective for plasma modification of the surface of the workpiece. At least part of the time while providing plasma, a magnetic field is provided in or near the plasma. The magnetic field has a position, orientation, and field strength effective to improve the uniformity, density, or both of plasma modification of the surface of the workpiece.

Still another aspect of the invention is apparatus for plasma modifying a workpiece supported on a workpiece support. The workpiece has a lumen surrounded by a wall, at least part of the wall defining a surface to be treated. The apparatus includes a workpiece support for holding a workpiece in the apparatus, a plasma generator, and a magnetic field generator.

The plasma generator provides plasma within the lumen of a workpiece supported on the workpiece support. The plasma is created or manipulated under conditions effective for plasma modification of the surface of the workpiece.

The magnetic field generator provides a magnetic field in at least a portion of the lumen of a workpiece supported on the workpiece support. The magnetic field has an orientation and field strength effective to improve the uniformity, density, or both of plasma modification of the interior surface of the generally cylindrical wall.

Yet another aspect of the invention is a pharmaceutical package of any type described in this specification, including a syringe barrel, cartridge barrel, or vial containing a pharmaceutical preparation, secured with a closure.

Other aspects of the invention are identified or apparent from the present specification and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevation view of a capped pre-assembly according to an embodiment of the disclosure.

FIG. 2 is a longitudinal section of the capped pre-assembly of FIG. 1.

FIG. 3 is an enlarged fragmentary view of the capped pre-assembly of FIGS. 1 and 2.

FIG. 4 is a schematic longitudinal section of the capped pre-assembly of FIGS. 1 and 2 seated on a chemical vapor deposition coating station.

FIG. 5 is a section taken along section lines AA of FIG. 4, showing a quadrupole magnet array.

FIG. 6 is a schematic view showing more details of the chemical vapor deposition coating station shown in FIGS. 4 and 5.

FIG. 7 is a view similar to FIG. 2 of the capped pre-assembly of FIGS. 1-6, filled with a pharmaceutical preparation and fitted with a plunger tip, piston, stopper, or seal to define a pre-filled syringe. In the option shown, a plunger tip, piston, stopper, or seal and plunger push rod are installed.

FIG. 8 is a longitudinal section of a vial fitted with a closure (septum and crimp) and having the same barrier coating or layer, passivation layer or pH protective coating, and other common features of FIG. 7.

FIG. 9 is a view similar to FIG. 5 of a solenoid coil as an alternative magnet structure usable with any embodiment of the invention.

FIG. 9a is an isolated perspective view of the solenoid coil in FIG. 9.

FIG. 10 is a view similar to FIG. 5 of a round-section toroidal coil as an alternative magnet structure usable with any embodiment of the invention.

FIG. 11 is an isolated cutaway perspective view of the toroidal coil in FIG. 10.

FIG. 12 is a view similar to FIG. 9a of a rectangular-section toroidal coil as an alternative magnet structure usable with any embodiment of the invention.

FIG. 13 is a section taken along section line 13-13 of FIG. 12.

FIG. 14 shows the polar axis orientation of a ring magnet having a pole axis coinciding with its cylindrical axis usable with any embodiment of the invention.

FIG. 15 shows the polar axis orientation of a round cylindrical bar magnet having a pole axis parallel to its longest dimension usable with any embodiment of the invention.

FIG. 16 shows the polar axis orientation of a square-section cylindrical bar magnet having a pole axis parallel to its longest dimension usable with any embodiment of the invention.

FIG. 17 shows the polar axis orientation of a multi-pole ring magnet (cutaway from a closed ring) having circumferential pole axes usable with any embodiment of the invention.

FIG. 18 shows the polar axis orientation of a bar magnet having a pole axis parallel to its shortest (thickness) dimension and perpendicular to its longest (length) dimension.

FIG. 19 is a perspective view of the quadrupole magnet array of FIG. 5, usable in any embodiment of the invention.

FIG. 20 is a perspective view of an axial magnet array, usable analogous to the magnet array of FIG. 19 in any embodiment of the invention.

FIG. 21 is a perspective view of a quadrupole magnet array, usable analogous to the magnet array of FIG. 19 in any embodiment of the invention..

FIG. 22 is a perspective view of stacked multipole segmented ring magnet array, usable analogous to the magnet array of FIG. 19 in any embodiment of the invention.

FIG. 23 is a perspective view of a stacked axial-pole ring magnet array, usable analogous to the magnet array of FIG. 19 in any embodiment of the invention..

FIG. 24 is a perspective view of a stacked quadrupole magnet array, usable analogous to the magnet array of FIG. 19 in any embodiment of the invention..

FIG. 25 is a perspective view of a quadrupole magnet array, usable analogous to the magnet array of FIG. 19 in any embodiment of the invention..

FIG. 26 is a side elevation of a first alternative gas inlet and electrode with a 90-degree perforation pattern, usable analogous to the corresponding structure 108 of FIG. 5 in any embodiment of the invention.

FIG. 27 is a side elevation of a second alternative gas inlet and electrode with a triangular or 120-degree perforation pattern, usable analogous to the corresponding structure 108 of FIG. 5 in any embodiment of the invention..

FIG. 28 is a side elevation of a third alternative gas inlet and electrode with a spiral or 45-degree perforation array, usable analogous to the corresponding structure 108 of FIG. 5 in any embodiment of the invention..

FIG. 29 is a perspective view of a medical sample tube, usable with the cap 270 removed on the PECVD apparatus of FIGS. 4-6 and 9-28 in any embodiment.

FIG. 30 is a plot of coating thickness versus position on the internal wall of a syringe barrel, in the experiment of Example 1.

FIG. 31 is a plot of coating thickness versus position on the internal wall of a syringe barrel, in the experiment of Example 2.

FIG. 32 is a plot of coating thickness versus position on the internal wall of a syringe barrel, in the experiment of Example 3.

FIG. 33 is a plot of coating thickness versus position on the internal wall of a syringe barrel, in the experiment of Example 4.

FIG. 34 is a plot of coating thickness versus position on the internal wall of a syringe barrel, in the experiment of Example 5.

FIG. 35 is a plot of coating thickness versus position on the internal wall of a syringe barrel, in the experiment of Example 6.

FIG. 36 is a longitudinal section of an auto injector assembly including a cartridge, which is a type of syringe barrel.

FIG. 37 is a view similar to FIG. 4 showing certain optional features usable separately or in combination in any embodiment, including a Helmholtz coil (86 a, 86 b), an optical detector (350), a Rogowski coil (352), and a Langmuir probe (354).

FIG. 38 is a schematic longitudinal section of plasma treatment apparatus including an electronic bottle. The plasma generation, material feed, and exhaust systems are omitted to better show the construction of the electronic bottle.

FIG. 39 is a section of FIG. 38 taken along section lines 39-39.

FIG. 40 is a partial section of FIG. 38 taken along section lines 40-40, showing cross sections of the ring magnet 75 and closely spaced magnetic lines 83.

FIG. 41 is a schematic section of an alternative electron bottle made of a stack of ring magnets 75 to provide radial confinement of electrons, capped on each end by a bar magnet 65 to provide axial confinement of electrons. The plasma generation, material feed, and exhaust systems are omitted to better show the construction of the electronic bottle.

FIG. 42 is a schematic section of an alternative electron bottle made of a solenoid coil to provide radial and axial confinement of electrons. The plasma generation, material feed, and exhaust systems are omitted to better show the construction of the electronic bottle.

FIG. 43 is a schematic section of yet another alternative electron bottle made of a solenoid to provide radial confinement of electrons and electrostatic electron mirrors to provide axial confinement of electrons. The plasma generation, material feed, and exhaust systems are omitted to better show the construction of the electronic bottle.

FIG. 44 is a schematic section of even another alternative electron bottle made of a cylindrical electrostatic mirror providing radial confinement of electrons and magnetic electron mirrors to provide axial confinement of electrons. The plasma generation, material feed, and exhaust systems are omitted to better show the construction of the electronic bottle.

FIG. 45 is a detail of an eight-magnet quadrupole analog made up of alternating bar magnets 61 and 62 having radially extending polar axes. The magnets 61 have the north pole oriented inward and the alternating magnets 62 have the north pole oriented outward.

FIG. 46 is a detail of a stack of eight ring magnets with their pole axes directed axially, as their annular faces define their poles. In one embodiment all eight have the same field strength, providing only radial confinement. In another embodiment the ring magnets on each end of the stack have a higher field strength, providing axial confinement too.

FIG. 47 is a schematic side view of a magnet array contemplated for use in certain aspects of the present invention.

FIG. 48 is a schematic side view of a vial in PECVD apparatus including a tilted quadrupole magnet array.

FIG. 49 is a perspective view of an axial magnet array contemplated for use in certain aspects of the present invention.

The following reference characters are used in the drawing figures:

10 Vial 12 Capped pre-assembly or workpiece 14 Barrel 16 Internal wall 18 Barrel lumen 20 Dispensing portion 22 Proximal opening 24 Distal opening 26 Dispensing portion lumen 27 Shield 30 Barrier coating or layer 32 Opening 34 Passivation layer or pH protective coating 36 plunger tip, piston, stopper, or seal 38 Push rod 40 Fluid material 42 Rib 44 Cylindrical surface 46 Barb 48 Catch 50 Vessel support 52 Plot 54 Plot 60 coating station 61 Quadro couple magnet 62 Quadro couple magnet 63 Quadro couple magnet 64 Quadro couple magnet 65 Axial magnet 66 Axial magnet 67 Axial magnet 68 Axial magnet 69 Axial magnet 70 Axial magnet 71 Axial magnet 72 Axial magnet 73 Segmented ring magnet 74 Segmented ring magnet 75 Axial ring magnet 76 Axial ring magnet 77 Axial ring magnet 78 Axial ring magnet 79 Polar axis of magnet 80 Axis of workpiece 81 Recess between magnets or within coil 82 Opening 83 Magnetic line 84 Closed end 85 First end (of 86) 86 Solenoid 87 Second end (of 86) 88 Toroid coil 89 First winding (of 86) 90 Toroid coil 91 Section (of 90) 92 Vessel port 93 Toroid alternate section (of 90) 94 Vacuum duct 95 Cross section (of 93) 96 Vacuum port 97 Second winding (of 86) (electron mirror) 98 Vacuum source 99 Third winding (of 86) (electron mirror) 100 O-ring (of 92) 101 Capacitor 102 O-ring (of 96) 103 Electron path 104 Gas inlet port 106 O-ring (of 100) 107 Shell electrode (−) 108 Probe (counter electrode) 109 Shell electrode (+) 110 Gas delivery port (of 108) 114 Housing (of 50) 116 Collar 118 Exterior surface (of 80) 120 End perforation 122 Side perforation 124 Side perforation 126 Bottom perforation 128 Top perforation 130 Side perforation 132 Side perforation 134 Top perforation 135 270° perforation 136 90° perforation 137 315° perforation 138 135° perforation 139 0° perforation 140 180° perforation 141 45° perforation 142 225° perforation 144 PECVD gas source 152 Pressure gauge 160 Electrode 162 Power supply 164 Sidewall (of 160) 166 Sidewall (of 160) 168 Closed end (of 160) 200 Electrode 210 Pharmaceutical package 268 Sample collection tube, e.g. blood collection tube 270 Cap 300 Auto injector syringe 350 Optical detector (350), for example a camera or an optical emissions spectrometer 352 Rogowski coil 354 Langmuir probe 404 Exhaust 574 Main vacuum valve 576 Vacuum line 578 Manual bypass valve 580 Bypass line 582 Vent valve 584 Main reactant gas valve 586 Main reactant feed line 588 Organosilicon liquid reservoir 590 Organosilicon feed line (capillary) 592 Organosilicon shut-off valve 594 Oxygen tank 596 Oxygen feed line 598 Mass flow controller 600 Oxygen shut-off valve 602 Additional reservoir 604 Feed line 606 Shut-off valve 614 Headspace 616 Pressure source 618 Pressure line 620 Capillary connection

DEFINITION SECTION

In the context of the present invention, the following definitions and abbreviations are used:

“Plasma,” unless otherwise indicated, refers to an energized state of matter similar to gas in which a certain portion of the particles of matter are ionized. “Plasma” in another context in this specification can instead refer to the liquid component of blood, but only if the latter meaning is clear from the context of the disclosure.

RF is radio frequency.

The term “at least” in the context of the present invention means “equal or more” than the integer following the term. The word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality unless indicated otherwise. Whenever a parameter range is indicated, it is intended to disclose the parameter values given as limits of the range and all values of the parameter falling within said range.

“First” and “second” or similar references to, for example, processing stations or processing devices refer to the minimum number of processing stations or devices that are present, but do not necessarily represent the order or total number of processing stations and devices. These terms do not limit the number of processing stations or the particular processing carried out at the respective stations.

For purposes of the present invention, an “organosilicon precursor” is a compound having at least one of the linkages:

which is a tetravalent silicon atom connected to an oxygen or nitrogen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom). A volatile organosilicon precursor, defined as such a precursor that can be supplied as a vapor in a PECVD apparatus, can be an optional organosilicon precursor. Optionally, the organosilicon precursor can be selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, an alkyl trimethoxysilane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors.

The feed amounts of PECVD precursors, gaseous reactant or process gases, and carrier gas are sometimes expressed in “standard volumes” in the specification and claims. The standard volume of a charge or other fixed amount of gas is the volume the fixed amount of the gas would occupy at a standard temperature and pressure (without regard to the actual temperature and pressure of delivery). Standard volumes can be measured using different units of volume, and still be within the scope of the present disclosure and claims. For example, the same fixed amount of gas could be expressed as the number of standard cubic centimeters, the number of standard cubic meters, or the number of standard cubic feet. Standard volumes can also be defined using different standard temperatures and pressures, and still be within the scope of the present disclosure and claims. For example, the standard temperature might be 0° C. and the standard pressure might be 760 Torr (as is conventional), or the standard temperature might be 20° C. and the standard pressure might be 1 Torr. But whatever standard is used in a given case, when comparing relative amounts of two or more different gases without specifying particular parameters, the same units of volume, standard temperature, and standard pressure are to be used relative to each gas, unless otherwise indicated.

The corresponding feed rates of PECVD precursors, gaseous reactant or process gases, and carrier gas are expressed in standard volumes per unit of time in the specification. For example, in the working examples the flow rates are expressed as standard cubic centimeters per minute, abbreviated as sccm. As with the other parameters, other units of time can be used, such as seconds or hours, but consistent parameters are to be used when comparing the flow rates of two or more gases, unless otherwise indicated.

A “vessel” in the context of the present invention can be any type of article with at least one opening and a wall defining an inner or interior surface. The substrate can be the inside wall of a vessel having a lumen. Though the invention is not necessarily limited to pharmaceutical packages or other vessels of a particular volume, pharmaceutical packages or other vessels are contemplated in which the lumen can have a void volume of from 0.5 to 50 mL, optionally from 1 to 10 mL, optionally from 0.5 to 5 mL, optionally from 1 to 3 mL. The substrate surface can be part or all of the inner or interior surface of a vessel having at least one opening and an inner or interior surface.

A vessel in the context of the present invention can have one or more openings. One or two openings, like the openings of a common type of blister package well, vial or sample tube (one opening) or a common type of syringe or cartridge barrel (two openings) are preferred. If the vessel has two openings, they can be the same size or different sizes. If there is more than one opening, one opening can be used for the gas inlet for a PECVD coating method according to the present invention, while the other openings are either capped or open. A vessel according to the present invention can be a sample tube, for example for collecting or storing biological fluids like blood or urine, a syringe (or a part thereof, for example a syringe barrel) for storing or delivering a biologically active compound or composition, for example a medicament or pharmaceutical composition, a vial for storing biological materials or biologically active compounds or compositions, a pipe, for example a catheter for transporting biological materials or biologically active compounds or compositions, or a cuvette for holding fluids, for example for holding biological materials or biologically active compounds or compositions.

The vessel can be provided with a reagent or preservative for sample collection (e.g. blood collection) or analysis. For example, a vessel for blood collection can have an inner or interior surface defining a lumen and an exterior surface, the passivation layer or pH protective coating can be on the inner or interior surface, and the vessel can contain a compound or composition in its lumen, for example citrate or a citrate containing composition.

A vessel can be of any shape, a vessel having a substantially cylindrical wall at or near at least one of its open ends being preferred. Generally, the interior wall of the vessel can be cylindrically shaped, like, for example in a sample tube or a syringe barrel. Sample tubes and syringes or their parts (for example syringe barrels) are contemplated.

A “hydrophobic layer” in the context of the present invention means that the coating or layer lowers the wetting tension of a surface coated with the coating or layer, compared to the corresponding uncoated surface. Hydrophobicity can be thus a function of both the uncoated substrate and the coating or layer. The same applies with appropriate alterations for other contexts wherein the term “hydrophobic” is used. The term “hydrophilic” means the opposite, i.e. that the wetting tension is increased compared to reference sample. The present hydrophobic layers are primarily defined by their hydrophobicity and the process conditions providing hydrophobicity. Suitable hydrophobic coatings or layers and their application, properties, and use are described in U.S. Pat. No. 7,985,188. Dual functional passivation layers or pH protective coatings that also have the properties of hydrophobic coatings or layers can be provided for any embodiment of the present invention.

The values of w, x, y, and z are applicable to the empirical composition Si_(w)O_(x)C_(y)H_(z) throughout this specification. The values of w, x, y, and z used throughout this specification should be understood as ratios or an empirical formula (for example for a coating or layer), rather than as a limit on the number or type of atoms in a molecule. For example, octamethylcyclotetrasiloxane, which has the molecular composition Si₄O₄C₈H₂₄, can be described by the following empirical formula, arrived at by dividing each of w, x, y, and z in the molecular formula by 4, the largest common factor: Si₁O₁C₂H₆. The values of w, x, y, and z are also not limited to integers. For example, (acyclic) octamethyltrisiloxane, molecular composition Si₃O₂C₈H₂₄, is reducible to Si₁O_(0.67)C_(2.67)H₈. Also, although SiO_(x)C_(y)H_(z) can be described as equivalent to SiO_(x)C_(y), it is not necessary to show the presence of hydrogen in any proportion to show the presence of SiO_(x)C_(y).

“Wetting tension” is a specific measure for the hydrophobicity or hydrophilicity of a surface. An optional wetting tension measurement method in the context of the present invention is ASTM D 2578 or a modification of the method described in ASTM D 2578. This method uses standard wetting tension solutions (called dyne solutions) to determine the solution that comes nearest to wetting a plastic film surface for exactly two seconds. This is the film's wetting tension. The procedure utilized can be varied herein from ASTM D 2578 in that the substrates are not flat plastic films, but are tubes made according to the Protocol for Forming PET Tube and (except for controls) coated according to the Protocol for coating Tube Interior with Hydrophobic Coating or Layer (see Example 9 of EP2251671 A2).

A “lubricity coating or layer” according to the present invention is a coating or layer which has a lower frictional resistance than the uncoated surface.

A “passivation layer or pH protective coating” according to the present invention passivates or protects an underlying surface or layer from a fluid composition contacting the layer (as more extensively defined elsewhere in this specification).

“Frictional resistance” can be static frictional resistance and/or kinetic frictional resistance.

One of the optional embodiments of the present invention can be a syringe part, for example a syringe barrel or plunger tip, piston, stopper, or seal, coated with a lubricity and/or passivation layer or pH protective coating. In this contemplated embodiment, the relevant static frictional resistance in the context of the present invention is the breakout force as defined herein, and the relevant kinetic frictional resistance in the context of the present invention is the plunger sliding force as defined herein. For example, the plunger sliding force as defined and determined herein is suitable to determine the presence or absence and the lubricity and/or passivating or protective characteristics of a lubricity and/or passivation layer or pH protective coating in the context of the present invention whenever the coating or layer is applied to any syringe or syringe part, for example to the inner wall of a syringe barrel. The breakout force can be of particular relevance for evaluation of the coating or layer effect on a prefilled syringe, i.e. a syringe which can be filled after coating and can be stored for some time, for example several months or even years, before the plunger tip, piston, stopper, or seal is moved again (has to be “broken out”).

The “plunger sliding force” (synonym to “glide force,” “maintenance force”, or Fm, also used in this description) in the context of the present invention is the force required to maintain movement of a plunger tip, piston, stopper, or seal in a syringe barrel, for example during aspiration or dispense. It can advantageously be determined using the ISO 7886-1:1993 test described herein and known in the art. A synonym for “plunger sliding force” often used in the art is “plunger force” or “pushing force”.

The “plunger breakout force” (synonym to “breakout force”, “break loose force”, “initation force”, Fi, also used in this description) in the context of the present invention is the initial force required to move the plunger tip, piston, stopper, or seal in a syringe, for example in a prefilled syringe.

Both “plunger sliding force” and “plunger breakout force” and methods for their measurement are described in more detail in subsequent parts of this description. These two forces can be expressed in N, lbs or kg and all three units are used herein. These units correlate as follows: 1N=0.102 kg=0.2248 lbs (pounds).

Sliding force and breakout force are sometimes used herein to describe the forces required to advance a stopper or other closure into a pharmaceutical package or other vessel, such as a medical sample tube or a vial, to seat the stopper in a vessel to close the vessel. Its use can be analogous to use in the context of a syringe and its plunger tip, piston, stopper, or seal, and the measurement of these forces for a vessel and its closure are contemplated to be analogous to the measurement of these forces for a syringe, except that at least in most cases no liquid is ejected from a vessel when advancing the closure to a seated position.

“Slidably” means that the plunger tip, piston, stopper, or seal or other removable part can be permitted to slide in a syringe barrel or other vessel.

An “electron bottle” is a virtual container made up of magnetic and/or electrical fields that tend to confine within it the electrons having less energy than necessary to escape the bottle. The electron bottle should not be confused with a workpiece or chamber that has walls confining the contents. Positively and/or negatively charged ions in the plasma may also be confined by the electron bottle, and often can be more easily confined than electrons due to their lower energy, so an “electron bottle” is specially defined here to include a structure that tends to direct or confine ions.

It will be appreciated by those skilled in the field that if the plasma is formed inside the walls of a container (whether the workpiece or a separate chamber), part of the confinement function can be performed by the container itself, and the electron bottle optionally can merely supplement that function. It will also be appreciated that the electron bottle and any physical container can coincide in space or not, and the magnetic container “walls” can be within the physical container, outside the physical container, intersect with a wall of the physical container, or different portions of it can be in any two or more of these positions at once.

Except to the extent the container in which the plasma is formed is made in part of ferromagnetic or ferrimagnetic material (for example a hypodermic needle of a syringe assembly), the container and the electron bottle may not substantially interact with each other. Moreover, an electron bottle need not necessarily provide 360-degree confinement of electrons or ions, as the goal is not necessarily to confine electrons or ions per se, but can be to improve the treatment of the workpiece. For example, when a vial, syringe barrel, or cartridge barrel is used with an electron bottle, the “bottle” optionally can be just a single axial electron mirror adjacent to one end of the vial, or adjacent to both ends of the vial, without substantial radial confinement. Alternatively, the “bottle” optionally can provide radial confinement, as by using the quadrupoles of FIG. 4-6, 21, 23, 25, 38-40 or 45 or uniformly wound coils, without adding substantial axial confinement.

DETAILED DESCRIPTION

The present invention will now be described more fully, with reference to the accompanying drawings, in which several embodiments are shown. This invention can, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth here. Rather, these embodiments are examples of the invention, which has the full scope indicated by the language of the claims. Like numbers refer to like or corresponding elements throughout. The following disclosure relates to all embodiments unless specifically limited to a certain embodiment.

Coatings of SiO_(x) are deposited by plasma enhanced chemical vapor deposition (PECVD) or other chemical vapor deposition processes on the vessel of a pharmaceutical package, in particular a thermoplastic package, to serve as a barrier coating or layer preventing oxygen, air, carbon dioxide, or other gases from entering the vessel and/or to prevent leaching of the pharmaceutical material into or through the package wall. The barrier coating or layer can be effective to reduce the ingress of atmospheric gas, for example oxygen, into the lumen compared to a vessel without a passivation layer or pH protective coating.

In any embodiment the vapor-deposited coating or layer optionally can also, or alternatively, be a solute barrier coating or layer. A concern of converting from glass to plastic syringes centers around the potential for leachable materials from plastics. With plasma coating technology, the coatings or layers derived from non-metal gaseous precursors, for example HMDSO or OMCTS or other organosilicon compounds, will contain no trace metals and function as a barrier coating or layer to inorganic, metals and organic solutes, preventing leaching of these species from the coated substrate into syringe fluids. In addition to leaching control of plastic syringes, the same plasma passivation layer or pH protective coating technology offers potential to provide a solute barrier to the plunger tip, piston, stopper, or seal, typically made of elastomeric plastic compositions containing even higher levels of leachable organic oligomers and catalysts.

Moreover, certain syringes prefilled with synthetic and biological pharmaceutical formulations are very oxygen and moisture sensitive. A critical factor in the conversion from glass to plastic syringe barrels will be the improvement of plastic oxygen and moisture barrier performance. The plasma passivation layer or pH protective coating technology can be suitable to maintain the SiO_(x) barrier coating or layer or layer for protection against oxygen and moisture over an extended shelf life.

Examples of solutes in drugs usefully excluded by a barrier layer in any embodiment include antibacterial preservatives, antioxidants, chelating agents, pH buffers, and combinations of any of these. In any embodiment the vapor-deposited coating or layer optionally can be a solvent barrier coating or layer for a solvent comprising a co-solvent used to increase drug solubilization.

In any embodiment the vapor-deposited coating or layer optionally can be a barrier coating or layer for water, glycerin, propylene glycol, methanol, ethanol, n-propanol, isopropanol, acetone, benzyl alcohol, polyethylene glycol, cotton seed oil, benzene, dioxane, or combinations of any two or more of these.

In any embodiment the vapor-deposited coating or layer optionally can be a metal ion barrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can be a barrel wall material barrier coating or layer, to prevent or reduce the leaching of barrel material such as any of the base barrel resins mentioned previously and any other ingredients in their respective compositions.

The inventors have found, however, that such barrier coatings or layers or coatings of SiO_(x) are eroded or dissolved by some fluid compositions, for example aqueous compositions having a pH above about 5. Since coatings applied by chemical vapor deposition can be very thin—tens to hundreds of nanometers thick even a relatively slow rate of erosion can remove or reduce the effectiveness of the barrier coating or layer in less time than the desired shelf life of a product package. This can be particularly a problem for fluid pharmaceutical compositions, since many of them have a pH of roughly 7, or more broadly in the range of 5 to 9, similar to the pH of blood and other human or animal fluids. The higher the pH of the pharmaceutical preparation, the more quickly it erodes or dissolves the SiO_(x) coating.

The inventors have further found that without a protective coating borosilicate glass surfaces are eroded or dissolved by some fluid compositions, for example aqueous compositions having a pH above about 5. This can be particularly a problem for fluid pharmaceutical compositions, since many of them have a pH of roughly 7, or more broadly in the range of 5 to 9, similar to the pH of blood and other human or animal fluids. The higher the pH of the pharmaceutical preparation, the more quickly it erodes or dissolves the glass. Delamination of the glass can also result from such erosion or dissolution, as small particles of glass are undercut by the aqueous compositions having a pH above about 5.

The inventors have further found that certain passivation layers or pH protective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) formed from cyclic polysiloxane precursors, which passivation layers or pH protective coatings have a substantial organic component, do not erode quickly when exposed to fluid compositions, and in fact erode or dissolve more slowly when the fluid compositions have higher pHs within the range of 5 to 9. For example, at pH 8, the dissolution rate of a passivation layer or pH protective coating made from the precursor octamethylcyclotetrasiloxane, or OMCTS, can be quite slow. These passivation layers or pH protective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) can therefore be used to cover a barrier coating or layer of SiO_(x), retaining the benefits of the barrier coating or layer by passivating or protecting it from the fluid composition in the pharmaceutical package. These passivation layers or pH protective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) also can be used to cover a glass surface, for example a borosilicate glass surface, preventing delamination, erosion and dissolution of the glass, by passivating or protecting it from the fluid composition in the pharmaceutical package.

Although the present invention does not depend upon the accuracy of the following theory, it is believed that the material properties of an effective SiO_(x)C_(y) passivation layer or pH protective coating and those of an effective lubricity layer as described in U.S. Pat. No. 7,985,188 and in International Application PCT/US11/36097 are similar in some instances, such that a coating having the characteristics of a lubricity layer as described in certain working examples of this specification, U.S. Pat. No. 7,985,188, or International Application PCT/US11/36097 will also in certain cases serve as well as a passivation layer or pH protective coating to passivate or protect the barrier coating or layer of the package and vice versa.

Although the present invention does not depend upon the accuracy of the following theory, it is further believed that the most effective lubricity and/or passivation layers or pH protective coatings are those made from cyclic siloxanes and silazanes as described in this disclosure. SiO_(x)C_(y) or SiN_(x)C_(y) coatings deposited from linear siloxane or linear silazane precursors, for example hexamethyldisiloxane (HMDSO), are believed to contain fragments of the original precursor to a large degree and low organic content. Such SiO_(x)C_(y) or SiN_(x)C_(y) coatings have a degree of water miscibility or swellability, allowing them to be attacked by aqueous solutions. SiO_(x)C_(y) or SiN_(x)C_(y) coatings deposited from cyclic siloxane or linear silazane precursors, for example octamethylcyclotetrasiloxane (OMCTS), however, are believed to include more intact cyclic siloxane rings and longer series of repeating units of the precursor structure. These coatings are believed to be nanoporous but structured and hydrophobic, and these properties are believed to contribute to their success as passivation layers or pH protective coatings. This is shown, for example, in U.S. Pat. No. 7,901,783.

PECVD Treated Pharmaceutical Packages or other Vessels

A vessel with a barrier layer and preferably a passivation layer or pH protective coating as described herein and/or prepared according to a method described herein can be used for reception and/or storage and/or delivery of a compound or composition. The compound or composition can be sensitive, for example air-sensitive, oxygen-sensitive, sensitive to humidity and/or sensitive to mechanical influences. It can be a biologically active compound or composition, for example a pharmaceutical preparation or medicament like insulin or a composition comprising insulin. A prefilled syringe can be especially considered which contains injectable or other liquid drugs like insulin.

In another aspect, the compound or composition can be a biological fluid, optionally a bodily fluid, for example blood or a blood fraction. In certain aspects of the present invention, the compound or composition can be a product to be administrated to a subject in need thereof, for example a product to be injected, like blood (as in transfusion of blood from a donor to a recipient or reintroduction of blood from a patient back to the patient) or insulin.

A vessel with a passivation layer or pH protective coating as described herein and/or prepared according to a method described herein can further be used for protecting a compound or composition contained in its interior space against mechanical and/or chemical effects of the surface of the vessel material. For example, it can be used for preventing or reducing precipitation and/or clotting or platelet activation of the compound or a component of the composition, for example insulin precipitation or blood clotting or platelet activation.

It can further be used for protecting a compound or composition contained in its interior against the environment outside of the pharmaceutical package or other vessel, for example by preventing or reducing the entry of one or more compounds from the environment surrounding the vessel into the interior space of the vessel. Such environmental compound can be a gas or liquid, for example an atmospheric gas or liquid containing oxygen, air, and/or water vapor.

Referring to the Figures, an aspect of the invention can be a method in which a barrier coating or layer 30 and a passivation layer or pH protective coating 34 are applied directly or indirectly applied to at least a portion of the interior wall 16 of a vessel, such as any of the pharmaceutical packages 210 of FIGS. 7-8 and 29, a sample collection tube, for example a blood collection tube and/or a closed-ended sample collection tube; a conduit; a cuvette; or a vessel part, for example a plunger tip, piston, stopper, or seal for contact with and/or storage and/or delivery of a compound or composition.

Vessel Wall Construction

Optionally for any of the embodiments of FIG. 7-8 or 29, at least a portion of the internal wall 16 of the pharmaceutical package 210 comprises or consists essentially of a polymer, for example a polyolefin (for example a cyclic olefin polymer, a cyclic olefin copolymer, or polypropylene), a polyester, for example polyethylene terephthalate or polyethylene naphthalate, a polycarbonate, polylactic acid, or any combination, composite or blend of any two or more of the above materials.

Optionally for any of the embodiments of FIGS. 7-8 and 29, at least a portion of the internal wall 16 of the pharmaceutical package 210 comprises or consists essentially of glass, for example borosilicate glass.

As an optional feature of any of the foregoing embodiments the polymeric material can be a silicone elastomer or a thermoplastic polyurethane, as two examples, or any material suitable for contact with blood, or with insulin. For example, the use of a coated substrate according to any described embodiment is contemplated for storing insulin.

Optionally, as for the embodiments of FIG. 7, the pharmaceutical package 210 comprises a syringe barrel.

Optionally, the pharmaceutical package comprises a cartridge.

Optionally, as for the embodiments of FIG. 8, the pharmaceutical package 210 comprises a vial.

Optionally, the pharmaceutical package 210 comprises a blister package or ampoule.

Optionally, the pharmaceutical package comprises a medical sample tube of FIG. 29.

Alternatively, the vessel can be a length of tubing from about 1 cm to about 200 cm, optionally from about 1 cm to about 150 cm, optionally from about 1 cm to about 120 cm, optionally from about 1 cm to about 100 cm, optionally from about 1 cm to about 80 cm, optionally from about 1 cm to about 60 cm, optionally from about 1 cm to about 40 cm, optionally from about 1 cm to about 30 cm long, and processing it with a probe electrode as described below. Particularly for the longer lengths in the above ranges, it is contemplated that relative motion between the PECVD or other chemical vapor deposition probe and the vessel can be useful during passivation layer or pH protective coating formation. This can be done, for example, by moving the vessel with respect to the probe or moving the probe with respect to the vessel.

In these embodiments, it is contemplated that the barrier coating or layer discussed below can be thinner or less complete than would be preferred to provide the high gas barrier integrity needed in an evacuated blood collection tube, while still providing the long shelf life needed to store a liquid material in contact with the barrier coating or layer for an extended period.

As an optional feature of any of the foregoing embodiments the vessel can have a central axis. As an optional feature of any of the foregoing embodiments the vessel wall can be sufficiently flexible to be flexed at least once at 20° C., without breaking the wall, over a range from at least substantially straight to a bending radius at the central axis of not more than 100 times as great as the outer diameter of the vessel.

As an optional feature of any of the foregoing embodiments the bending radius at the central axis can be, for example, not more than 90 times as great as, or not more than 80 times as great as, or not more than 70 times as great as, or not more than 60 times as great as, or not more than 50 times as great as, or not more than 40 times as great as, or not more than 30 times as great as, or not more than 20 times as great as, or not more than 10 times as great as, or not more than 9 times as great as, or not more than 8 times as great as, or not more than 7 times as great as, or not more than 6 times as great as, or not more than 5 times as great as, or not more than 4 times as great as, or not more than 3 times as great as, or not more than 2 times as great as, or not more than, the outer diameter of the vessel.

As an optional feature of any of the foregoing embodiments the vessel wall can be a fluid-contacting surface made of flexible material.

As an optional feature of any of the foregoing embodiments the vessel lumen can be the fluid flow passage of a pump.

As an optional feature of any of the foregoing embodiments the vessel can be a blood containing vessel. The passivation layer or pH protective coating can be effective to reduce the clotting or platelet activation of blood exposed to the inner or interior surface, compared to the same type of wall uncoated with a hydrophobic layer.

It is contemplated that the incorporation of a hydrophobic layer will reduce the adhesion or clot forming tendency of the blood, as compared to its properties in contact with an unmodified polymeric or SiO_(x) surface. This property is contemplated to reduce or potentially eliminate the need for treating the blood with heparin, as by reducing the necessary blood concentration of heparin in a patient undergoing surgery of a type requiring blood to be removed from the patient and then returned to the patient, as when using a heart-lung machine during cardiac surgery. It is contemplated that this will reduce the complications of surgery involving the passage of blood through such a pharmaceutical package or other vessel, by reducing the bleeding complications resulting from the use of heparin.

Another embodiment can be a vessel including a wall and having an inner or interior surface defining a lumen. The inner or interior surface can have an at least partial passivation layer or pH protective coating that presents a hydrophobic surface, the thickness of the passivation layer or pH protective coating being from monomolecular thickness to about 1000 nm thick on the inner or interior surface, the passivation layer or pH protective coating being effective to reduce the clotting or platelet activation of blood exposed to the inner or interior surface.

Several non-limiting examples of such a vessel are a blood transfusion bag, a blood sample collection tube (e.g. blood collection tube) or other vessel in which a sample has been collected, the tubing of a heart-lung machine, a flexible-walled blood collection bag, or tubing used to collect a patient's blood during surgery and reintroduce the blood into the patient's vasculature. If the vessel includes a pump for pumping blood, a particularly suitable pump can be a centrifugal pump or a peristaltic pump. The vessel can have a wall; the wall can have an inner or interior surface defining a lumen. The inner or interior surface of the wall can have an at least partial passivation layer or pH protective coating of a protective layer, which optionally also presents a hydrophobic surface. The passivation layer or pH protective coating can be as thin as monomolecular thickness or as thick as about 1000 nm. Optionally, the vessel can contain blood viable for return to the vascular system of a patient disposed within the lumen in contact with the hydrophobic layer.

An embodiment can be a blood containing vessel including a wall and having an inner or interior surface defining a lumen. The inner or interior surface can have an at least partial passivation layer or pH protective coating that optionally also presents a hydrophobic surface. The passivation layer or pH protective coating can also comprise or consist essentially of SiO_(x)C_(y) where x and y are as defined in this specification. The vessel contains blood viable for return to the vascular system of a patient disposed within the lumen in contact with the hydrophobic coating or layer.

An embodiment can be carried out under conditions effective to form a hydrophobic passivation layer or pH protective coating on the substrate. Optionally, the hydrophobic characteristics of the passivation layer or pH protective coating can be set by setting the ratio of the oxidizing gas to the organosilicon precursor in the gaseous reactant, and/or by setting the electric power used for generating the plasma. Optionally, the passivation layer or pH protective coating can have a lower wetting tension than the uncoated surface, optionally a wetting tension of from 20 to 72 dyne/cm, optionally from 30 to 60 dynes/cm, optionally from 30 to 40 dynes/cm, optionally 34 dyne/cm. Optionally, the passivation layer or pH protective coating can be more hydrophobic than the uncoated surface.

In an optional embodiment, the vessel can have an inner diameter of at least 2 mm, or at least 4 mm.

As an optional feature of any of the foregoing embodiments the vessel can be a tube.

As an optional feature of any of the foregoing embodiments the lumen can have at least two open ends.

Syringe

The vessel of FIGS. 1-7 is a syringe, which is a contemplated type of vessel provided with a barrier layer and a passivation layer or pH protective coating. The syringe can comprise a syringe barrel 14 and a plunger tip, piston, stopper, or seal 36. The internal wall 16 can define at least a portion of the syringe barrel 250. The plunger tip, piston, stopper, or seal 36 can be a relatively sliding part of the syringe, with respect to the syringe barrel 250. The term “syringe” is broadly defined to include cartridges, injection “pens,” and other types of barrels or reservoirs adapted to be assembled with one or more other components to provide a functional syringe. A “syringe” is also broadly defined to include related articles such as auto-injectors, which provide a mechanism for dispensing the contents.

As one non-limiting way to make the syringe, a capped pre-assembly 12 can be provided comprising a barrel 14, a dispensing portion 20, and a shield 28. The capped pre-assembly 12 can be a complete article or it can be a portion of a complete article adapted to dispense fluid, such as a syringe, a cartridge, a catheter, or other article.

The barrel 14 can have an internal wall 16 defining a barrel lumen 18. Optionally in any embodiment, the barrel 14 can further include an opening 32 spaced from the dispensing portion 20 and communicating through the internal wall 16. Such an opening can be conventional, for example, in a syringe or cartridge, where a typical example can be the back opening 32 of a prefilled syringe barrel, through which the plunger tip, piston, stopper, or seal 36 can be inserted after the barrel lumen 18 is filled with a suitable pharmaceutical preparation or other fluid material 40 to be dispensed.

The barrel 14 can be formed, for example, by molding, although the manner of its formation is not critical and it can also be formed, for example, by machining a solid preform. Preferably, the barrel can be molded by injection molding thermoplastic material, although it can also be formed by blow molding or a combined method.

As one preferred example, the barrel 14 can be formed by placing a dispensing portion 20 as described below in an injection mold and injection molding thermoplastic material about the dispensing portion, thus forming the barrel and securing the dispensing portion to the barrel. Alternatively, the dispensing portion and the barrel can be molded or otherwise formed as a single piece, or can be formed separately and joined in other ways. The barrel of any embodiment can be made of any suitable material. Several barrel materials particularly contemplated are COC (cyclic olefin copolymer), COP (cyclic olefin polymer), PET (polyethylene terephthalate), and polypropylene.

The dispensing portion 20 of the capped pre-assembly 12 can be provided to serve as an outlet for fluid dispensed from the barrel lumen 18 of a completed article made from the capped pre-assembly 12. One example of a suitable dispensing portion illustrated in the Figures can be a hypodermic needle.

Alternatively, in any embodiment the dispensing portion 20 can instead be a needle-free dispenser. One example of a suitable needle-free dispenser can be a blunt or flexible dispensing portion intended to be received in a complementary coupling to transfer fluid material 40. Such blunt or flexible dispensing portions are well known for use in syringes, intravenous infusion systems, and other systems and equipment to dispense material while avoiding the hazard of working with a sharp needle that may accidentally stick a health professional or other person. Another example of a needle-free dispenser can be a fluid jet or spray injection system that injects a free jet or spray of fluid directly through a patient's skin, without the need for an intermediate needle. Any type of dispensing portion 20, whether a hypodermic needle or any form of needle-free dispenser, is contemplated for use according to any embodiment of the present invention.

The dispensing portion 20 is or can be secured to the barrel 14 and includes a proximal opening 22, a distal opening 24, and a dispensing portion lumen 26. The proximal opening 22 communicates with the barrel lumen 18. The distal opening 24 can be located outside the barrel 14. The dispensing portion lumen 26 communicates between the proximal and distal openings 22, 24 of the dispensing portion 20. In the illustrated embodiment, the distal opening 24 can be at the sharpened tip of a hypodermic needle 20.

The shield 28 can be secured to the barrel 14 and at least substantially isolates the distal opening 24 of the dispensing portion 20 from pressure conditions outside the shield 28. Optionally in any embodiment, the shield 28 sufficiently isolates portions of the assembly 12 to provide a sufficient bio-barrier to facilitate safe use of the capped pre-assembly 12 for transdermal injections.

The shield 28 can isolate the distal opening 24 in various ways. Effective isolation can be provided at least partially due to contact between the shield 28 and the distal opening 24, as shown in present FIGS. 2, 3, 4, and 7. In the illustrated embodiment, the tip of the dispensing portion 20 can be buried in the material of the shield 28. Alternatively in any embodiment, effective isolation can be provided at least partially due to contact between the shield 28 and the barrel 14, as also shown in present FIGS. 2, 3, 4, and 7. In the illustrated embodiment, the primary line of contact between the shield 28 and the barrel 14 can be at a rib 42 (best seen in FIG. 3) encircling and seated against a generally cylindrical surface 44 at the nose of the barrel 14. Alternatively in any embodiment, effective isolation can be provided due to both of these types of contact as illustrated in FIGS. 2-3, or in other ways, without limitation.

The shield 28 of any embodiment optionally can have a latching mechanism, best shown in FIG. 3, including a barb 46 and a catch 48 which engage to hold the shield 28 in place. The catch 48 can be made of sufficiently resilient material to allow the shield 28 to be removed and replaced easily.

If the dispensing portion 20 is a hypodermic needle, the shield 28 can be a specially formed needle shield. The original use of a needle shield is to cover the hypodermic needle before use, preventing accidental needle sticks and preventing contamination of the needle before it is injected in a patient or an injection port. A comparable shield preferably is used, even if the dispensing portion 20 is a needle-free dispenser, to prevent contamination of the dispenser during handling.

The shield 28 can be formed in any suitable way. For example, the shield 28 can be formed by molding thermoplastic material. Optionally in any embodiment, the thermoplastic material can be elastomeric material or other material that can be suitable for forming a seal. One suitable category of elastomeric materials is known generically as thermoplastic elastomer (TPE). An example of a suitable thermoplastic elastomer for making a shield 28 is Stelmi® Formulation 4800 (flexible shield formulation). Any other material having suitable characteristics can instead be used in any embodiment.

As another optional feature in any embodiment the shield 28 can be sufficiently permeable to a sterilizing gas to sterilize the portions of the assembly 12 isolated by the shield. One example of a suitable sterilizing gas is ethylene oxide. Shields 28 are available that are sufficiently permeable to the sterilizing gas that parts isolated by the shield can nonetheless be sterilized. An example of a shield formulation sufficiently permeable to accommodate ethylene oxide gas sterilization can be Stelmi® Formulation 4800.

Coatings of SiO_(x) are deposited by plasma enhanced chemical vapor deposition (PECVD) or other chemical vapor deposition processes on the vessel of a pharmaceutical package, in particular a thermoplastic package, to serve as a barrier coating or layer preventing oxygen, air, carbon dioxide, or other gases from entering the vessel and/or to prevent leaching of the pharmaceutical material into or through the package wall. The barrier coating or layer can be effective to reduce the ingress of atmospheric gas, for example oxygen, into the lumen compared to a vessel without a passivation layer or pH protective coating.

In any embodiment the vapor-deposited coating or layer optionally can also, or alternatively, be a solute barrier coating or layer. A concern of converting from glass to plastic syringes centers around the potential for leachable materials from plastics. With plasma coating technology, the coatings or layers derived from non-metal gaseous precursors, for example HMDSO or OMCTS or other organosilicon compounds, will contain no trace metals and function as a barrier coating or layer to inorganic (e.g. metal) and organic solutes, preventing leaching of these species from the coated substrate into syringe fluids. In addition to leaching control of plastic syringes, the same plasma passivation layer or pH protective coating technology offers potential to provide a solute barrier to the plunger tip, piston, stopper, or seal, typically made of elastomeric plastic compositions containing even higher levels of leachable organic oligomers and catalysts.

Moreover, certain syringes prefilled with synthetic and biological pharmaceutical formulations are very oxygen and moisture sensitive. A critical factor in the conversion from glass to plastic syringe barrels will be the improvement of plastic oxygen and moisture barrier performance. The plasma passivation layer or pH protective coating technology can be suitable to maintain the SiO_(x) barrier coating or layer or layer for protection against oxygen and moisture over an extended shelf life.

Examples of solutes in drugs usefully excluded by a barrier layer in any embodiment include antibacterial preservatives, antioxidants, chelating agents, pH buffers, and combinations of any of these. In any embodiment the vapor-deposited coating or layer optionally can be a solvent barrier coating or layer for a solvent comprising a co-solvent used to increase drug solubilization.

In any embodiment the vapor-deposited coating or layer optionally can be a barrier coating or layer for water, glycerin, propylene glycol, methanol, ethanol, n-propanol, isopropanol, acetone, benzyl alcohol, polyethylene glycol, cotton seed oil, benzene, dioxane, or combinations of any two or more of these.

In any embodiment the vapor-deposited coating or layer optionally can be a metal ion barrier coating or layer.

In any embodiment the vapor-deposited coating or layer optionally can be a barrel wall material barrier coating or layer, to prevent or reduce the leaching of barrel material such as any of the base barrel resins mentioned previously and any other ingredients in their respective compositions.

The inventors have found, however, that such barrier coatings or layers or coatings of SiO_(x) are eroded or dissolved by some fluid compositions, for example aqueous compositions having a pH above about 5. Since coatings applied by chemical vapor deposition can be very thin—tens to hundreds of nanometers thick even a relatively slow rate of erosion can remove or reduce the effectiveness of the barrier coating or layer in less time than the desired shelf life of a product package. This can be particularly a problem for fluid pharmaceutical compositions, since many of them have a pH of roughly 7, or more broadly in the range of 5 to 9, similar to the pH of blood and other human or animal fluids. The higher the pH of the pharmaceutical preparation, the more quickly it erodes or dissolves the SiO_(x) coating.

The inventors have further found that without a protective coating borosilicate glass surfaces are eroded or dissolved by some fluid compositions, for example aqueous compositions having a pH above about 5. This can be particularly a problem for fluid pharmaceutical compositions, since many of them have a pH of roughly 7, or more broadly in the range of 5 to 9, similar to the pH of blood and other human or animal fluids. The higher the pH of the pharmaceutical preparation, the more quickly it erodes or dissolves the glass. Delamination of the glass can also result from such erosion or dissolution, as small particles of glass are undercut by the aqueous compositions having a pH above about 5.

The inventors have further found that certain passivation layers or pH protective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) formed from cyclic polysiloxane precursors, which passivation layers or pH protective coatings have a substantial organic component, do not erode quickly when exposed to fluid compositions, and in fact erode or dissolve more slowly when the fluid compositions have higher pHs within the range of 5 to 9. For example, at pH 8, the dissolution rate of a passivation layer or pH protective coating made from the precursor octamethylcyclotetrasiloxane, or OMCTS, can be quite slow. These passivation layers or pH protective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) can therefore be used to cover a barrier coating or layer of SiO_(x), retaining the benefits of the barrier coating or layer by passivating or protecting it from the fluid composition in the pharmaceutical package. These passivation layers or pH protective coatings of SiO_(x)C_(y) or SiN_(x)C_(y) also can be used to cover a glass surface, for example a borosilicate glass surface, preventing delamination, erosion and dissolution of the glass, by passivating or protecting it from the fluid composition in the pharmaceutical package.

Although the present invention does not depend upon the accuracy of the following theory, it is believed that the material properties of an effective SiO_(x)C_(y) passivation layer or pH protective coating and those of an effective lubricity layer as described in U.S. Pat. No. 7,985,188 and in International Application PCT/US11/36097 are similar in some instances, such that a coating having the characteristics of a lubricity layer as described in certain working examples of this specification, U.S. Pat. No. 7,985,188, or International Application PCT/US11/36097 will also in certain cases serve as well as a passivation layer or pH protective coating to passivate or protect the barrier coating or layer of the package and vice versa.

Although the present invention does not depend upon the accuracy of the following theory, it is further believed that the most effective lubricity and/or passivation layers or pH protective coatings are those made from cyclic siloxanes and silazanes as described in this disclosure. SiO_(x)C_(y) or SiN_(x)C_(y) coatings deposited from linear siloxane or linear silazane precursors, for example hexamethyldisiloxane (HMDSO), are believed to contain fragments of the original precursor to a large degree and low organic content. Such SiO_(x)C_(y) or SiN_(x)C_(y) coatings have a degree of water miscibility or swellability, allowing them to be attacked by aqueous solutions. SiO_(x)C_(y) or SiN_(x)C_(y) coatings deposited from cyclic siloxane or linear silazane precursors, for example octamethylcyclotetrasiloxane (OMCTS), however, are believed to include more intact cyclic siloxane rings and longer series of repeating units of the precursor structure. These coatings are believed to be nanoporous but structured and hydrophobic, and these properties are believed to contribute to their success as passivation layers or pH protective coatings. This is shown, for example, in U.S. Pat. No. 7,901,783.

Three embodiments of the invention having many common features are those of FIGS. 7, 8 and 29. Some of their common features are the following, indicated in many cases by common reference characters or names. The nature of the features of each embodiment can be as described later in the specification.

The pharmaceutical packages of FIGS. 7-8 and 29 each include a vessel 210, a fluid composition 40, an SiO_(x) barrier coating or layer 30, and a passivation layer or pH protective coating 34. Each vessel 210 can have a lumen 18 defined at least in part by a wall interior portion 16 made of thermoplastic material.

The internal wall 16 can have an interior surface 254 facing the lumen 18 and an outer surface 216.

The fluid composition 40 can be contained in the lumen 18 and can have a pH between 4 and 10, alternatively between 5 and 9.

Barrier Coating or Layer

In the filled pharmaceutical package or other vessel 210 the barrier coating or layer 30 can be located between the inner or interior surface of the thermoplastic internal wall 16 and the fluid material 40. The barrier coating or layer 286 of SiO_(x) can be supported by the thermoplastic internal wall 16. The barrier coating or layer 286 can have the characteristic of being subject to being measurably diminished in barrier improvement factor in less than six months as a result of attack by the fluid material 40. The barrier coating or layer 286 as described elsewhere in this specification, or in U.S. Pat. No. 7,985,188, can be used in any embodiment.

The barrier coating or layer 30 can be effective to reduce the ingress of atmospheric gas into the lumen 18, compared to an uncoated container otherwise the same as the pharmaceutical package or other vessel 210. The barrier coating or layer for any embodiment defined in this specification (unless otherwise specified in a particular instance) is optionally applied by PECVD as indicated in U.S. Pat. No. 7,985,188.

The barrier improvement factor (BIF) of the barrier coating or layer can be determined by providing two groups of identical containers, adding a barrier coating or layer to one group of containers, testing a barrier property (such as the rate of outgassing in micrograms per minute or another suitable measure) on containers having a barrier coating or layer, doing the same test on containers lacking a barrier coating or layer, and taking a ratio of the properties of the materials with versus without a barrier coating or layer. For example, if the rate of outgassing through the barrier coating or layer is one-third the rate of outgassing without a barrier coating or layer, the barrier coating or layer has a BIF of 3.

The barrier coating or layer optionally can be characterized as an “SiO_(x)” coating, and contains silicon, oxygen, and optionally other elements, in which x, the ratio of oxygen to silicon atoms, can be from about 1.5 to about 2.9, or 1.5 to about 2.6, or about 2. These alternative definitions of x apply to any use of the term SiO_(x) in this specification. The barrier coating or layer can be applied, for example to the interior of a pharmaceutical package or other vessel, for example a sample collection tube (e.g. a blood collection tube), a syringe barrel, a vial, or another type of vessel.

The barrier coating or layer 30 comprises or consists essentially of SiO_(x), from 2 to 1000 nm thick, the barrier coating or layer 30 of SiO_(x) having an interior surface facing the lumen 18 and an outer surface facing the internal wall 16. The barrier coating or layer 30 can be effective to reduce the ingress of atmospheric gas into the lumen 18 compared to an uncoated pharmaceutical package 210. One suitable barrier composition can be one where x is 2.3, for example.

For example, the barrier coating or layer such as 30 of any embodiment can be applied at a thickness of at least 2 nm, or at least 4 nm, or at least 7 nm, or at least 10 nm, or at least 20 nm, or at least 30 nm, or at least 40 nm, or at least 50 nm, or at least 100 nm, or at least 150 nm, or at least 200 nm, or at least 300 nm, or at least 400 nm, or at least 500 nm, or at least 600 nm, or at least 700 nm, or at least 800 nm, or at least 900 nm. The barrier coating or layer can be up to 1000 nm, or at most 900 nm, or at most 800 nm, or at most 700 nm, or at most 600 nm, or at most 500 nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or at most 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm, or at most 60 nm, or at most 50 nm, or at most 40 nm, or at most 30 nm, or at most 20 nm, or at most 10 nm, or at most 5 nm thick. Specific thickness ranges composed of any one of the minimum thicknesses expressed above, plus any equal or greater one of the maximum thicknesses expressed above, are expressly contemplated. Another contemplated thickness range is 20-80nm for the barrier coating or layer. The desired variation in thickness of the barrier coating or layer is +/−30% from the mean thickness, more preferably +/−15% from the mean thickness and most preferably, +/−5% from the mean thickness. The thickness of the SiO_(x) or other barrier coating or layer can be measured, for example, by transmission electron microscopy (TEM), and its composition can be measured by X-ray photoelectron spectroscopy (XPS). The passivation layer or pH protective coating described herein can be applied to a variety of pharmaceutical packages or other vessels made from plastic or glass, for example to plastic tubes, vials, and syringes.

Passivation Layer or pH Protective Coating

A passivation layer or pH protective coating 34 of SiO_(x)C_(y) can be applied, for example, by PECVD directly or indirectly to the barrier coating or layer 30 so it can be located between the barrier coating or layer 30 and the fluid material 40 in the finished article. The passivation layer or pH protective coating 34 can have an interior surface facing the lumen 18 and an outer surface facing the interior surface of the barrier coating or layer 30. The passivation layer or pH protective coating 34 can be supported by the thermoplastic internal wall 16. The passivation layer or pH protective coating 34 can be effective to keep the barrier coating or layer 30 at least substantially undissolved as a result of attack by the fluid material 40 for a period of at least six months, in one non-limiting embodiment.

Optionally, the passivation layer or pH protective coating can be composed of Si_(w)O_(x)C_(y)H_(z) (or its equivalent SiO_(x)C_(y)) or Si_(w)N_(x)C_(y)H_(z) or its equivalent SiN_(x)C_(y)), each as defined in this specification. Taking into account the H atoms, the passivation layer or pH protective coating may thus in one aspect have the formula Si_(w)O_(x)C_(y)H_(z), or its equivalent SiO_(x)C_(y), for example where w is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and z (if defined) is from about 2 to about 9.

The atomic ratio can be determined by XPS (X-ray photoelectron spectroscopy). XPS does not detect hydrogen atoms, so it is customary, when determining the atomic ratio by XPS, to omit hydrogen from the stated formulation. The formulation thus can be typically expressed as Si_(w)O_(x)C_(y) or SiO_(x)C_(y), where w is 1, x is from about 0.5 to about 2.4, and y is from about 0.6 to about 3, with no limitation on z.

The atomic ratios of Si, O, and C in the “lubricity and/or passivation layer or pH protective coating” can be, as several options:

Si 100:O 50-150: C 90-200 (i.e. w=1, x=0.5 to 1.5, y=0.9 to 2);

Si 100:O 70-130: C 90-200 (i.e. w=1, x=0.7 to 1.3, y=0.9 to 2)

Si 100:O 80-120: C 90-150 (i.e. w=1, x=0.8 to 1.2, y=0.9 to 1.5)

Si 100:O 90-120: C 90-140 (i.e. w=1, x=0.9 to 1.2, y=0.9 to 1.4), or

Si 100:O 92-107: C 116-133 (i.e. w=1, x=0.92 to 1.07, y=1.16 to 1.33)

Typically, such a coating or layer would contain 36% to 41% carbon normalized to 100% carbon plus oxygen plus silicon. Alternatively, the passivation layer or pH protective coating can have atomic concentrations normalized to 100% carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS) of less than 50% carbon and more than 25% silicon. Alternatively, the atomic concentrations can be from 25 to 45% carbon, 25 to 65% silicon, and 10 to 35% oxygen. Alternatively, the atomic concentrations can be from 30 to 40% carbon, 32 to 52% silicon, and 20 to 27% oxygen. Alternatively, the atomic concentrations can be from 33 to 37% carbon, 37 to 47% silicon, and 22 to 26% oxygen.

Optionally, the atomic concentration of carbon in the protective layer, normalized to 100% of carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS), can be greater than the atomic concentration of carbon in the atomic formula for the organosilicon precursor. For example, embodiments are contemplated in which the atomic concentration of carbon increases by from 1 to 80 atomic percent, alternatively from 10 to 70 atomic percent, alternatively from 20 to 60 atomic percent, alternatively from 30 to 50 atomic percent, alternatively from 35 to 45 atomic percent, alternatively from 37 to 41 atomic percent.

Optionally, the atomic ratio of carbon to oxygen in the passivation layer or pH protective coating can be increased in comparison to the organosilicon precursor, and/or the atomic ratio of oxygen to silicon can be decreased in comparison to the organosilicon precursor.

Optionally, the passivation layer or pH protective coating can have an atomic concentration of silicon, normalized to 100% of carbon, oxygen, and silicon, as determined by X-ray photoelectron spectroscopy (XPS), less than the atomic concentration of silicon in the atomic formula for the feed gas. For example, embodiments are contemplated in which the atomic concentration of silicon decreases by from 1 to 80 atomic percent, alternatively by from 10 to 70 atomic percent, alternatively by from 20 to 60 atomic percent, alternatively by from 30 to 55 atomic percent, alternatively by from 40 to 50 atomic percent, alternatively by from 42 to 46 atomic percent.

As another option, a passivation layer or pH protective coating is contemplated that can be characterized by a sum formula wherein the atomic ratio C:O can be increased and/or the atomic ratio Si:O can be decreased in comparison to the sum formula of the organosilicon precursor.

The passivation layer or pH protective coating can have a density between 1.25 and 1.65 g/cm³, alternatively between 1.35 and 1.55 g/cm³, alternatively between 1.4 and 1.5 g/cm³, alternatively between 1.4 and 1.5 g/cm³, alternatively between 1.44 and 1.48 g/cm³, as determined by X-ray reflectivity (XRR). Optionally, the organosilicon compound can be octamethylcyclotetrasiloxane and the passivation layer or pH protective coating can have a density which can be higher than the density of a passivation layer or pH protective coating made from HMDSO as the organosilicon compound under the same PECVD reaction conditions.

The passivation layer or pH protective coating optionally can have an RMS surface roughness value (measured by AFM) of from about 2 to about 9, optionally from about 6 to about 8, optionally from about 6.4 to about 7.8. The Ra surface roughness value of the passivation layer or pH protective coating, measured by AFM, can be from about 4 to about 6, optionally from about 4.6 to about 5.8. The R_(max) surface roughness value of the passivation layer or pH protective coating, measured by AFM, can be from about 70 to about 160, optionally from about 84 to about 142, optionally from about 90 to about 130.

The rate of erosion, dissolution, or leaching (different names for related concepts) of the construction including a passivation layer or pH protective coating 34, if directly contacted by the fluid material 40, can be less than the rate of erosion, dissolution, or leaching of the barrier coating or layer 30, if directly contacted by the fluid material 40.

The passivation layer or pH protective coating 34 can be effective to isolate or protect the barrier coating or layer 30 from the fluid material 40 at least for sufficient time to allow the barrier coating or layer to act as a barrier during the shelf life of the pharmaceutical package or other vessel 210.

Optionally an FTIR absorbance spectrum of the passivation layer or pH protective coating 34 of any embodiment of FIG. 7-8 or 29 can have a ratio greater than 0.75 between the maximum amplitude of the Si—O—Si symmetrical stretch peak normally located between about 1000 and 1040 cm⁻¹, and the maximum amplitude of the Si—O—Si asymmetric stretch peak normally located between about 1060 and about 1100 cm⁻¹. Alternatively in any embodiment, this ratio can be at least 0.8, or at least 0.9, or at least 1.0, or at least 1.1, or at least 1.2. Alternatively in any embodiment, this ratio can be at most 1.7, or at most 1.6, or at most 1.5, or at most 1.4, or at most 1.3. Any minimum ratio stated here can be combined with any maximum ratio stated here, as an alternative embodiment of the invention of FIGS. 7-8 and 29.

Optionally, in any embodiment of FIGS. 7-8 and 29 the passivation layer or pH protective coating, in the absence of the medicament, can have a non-oily appearance. This appearance has been observed in some instances to distinguish an effective passivation layer or pH protective coating from a lubricity layer, which in some instances has been observed to have an oily (i.e. shiny) appearance.

Optionally, in any embodiment of FIGS. 7-8 and 29 the silicon dissolution rate by a 50 mm potassium phosphate buffer diluted in water for injection, adjusted to pH 8 with concentrated nitric acid, and containing 0.2 wt. % polysorbate-80 surfactant, (measured in the absence of the medicament, to avoid changing the dissolution reagent), at 40° C., can be less than 170 ppb/day. (Polysorbate-80 is a common ingredient of pharmaceutical preparations, available for example as Tween®-80 from Uniqema Americas LLC, Wilmington Del.) As was done in the working examples, the silicon dissolution rate can be measured by determining the total silicon leached from the vessel into its contents, and does not distinguish between the silicon derived from the passivation layer or pH protective coating 34, the lubricity layer 287, the barrier coating or layer 30, or other materials present.

Optionally, in any embodiment of FIGS. 7-8 and 29 the silicon dissolution rate can be less than 160 ppb/day, or less than 140 ppb/day, or less than 120 ppb/day, or less than 100 ppb/day, or less than 90 ppb/day, or less than 80 ppb/day. Optionally, in any embodiment of FIGS. 7-8 and 29 the silicon dissolution rate can be more than 10 ppb/day, or more than 20 ppb/day, or more than 30 ppb/day, or more than 40 ppb/day, or more than 50 ppb/day, or more than 60 ppb/day. Any minimum rate stated here can be combined with any maximum rate stated here, as an alternative embodiment of the invention of FIGS. 7-8 and 29.

Optionally, in any embodiment of FIGS. 7-8 and 29 the total silicon content of the passivation layer or pH protective coating and barrier coating or layer, upon dissolution into a test composition with a pH of 8 from the vessel, can be less than 66 ppm, or less than 60 ppm, or less than 50 ppm, or less than 40 ppm, or less than 30 ppm, or less than 20 ppm.

Optionally, in any embodiment of FIGS. 7-8 and 29 the calculated shelf life of the package (total Si/Si dissolution rate) can be more than six months, or more than 1 year, or more than 18 months, or more than 2 years, or more than 2½ years, or more than 3 years, or more than 4 years, or more than 5 years, or more than 10 years, or more than 20 years. Optionally, in any embodiment of FIGS. 7-8 and 29 the calculated shelf life of the package (total Si/Si dissolution rate) can be less than 60 years.

Any minimum time stated here can be combined with any maximum time stated here, as an alternative embodiment of the invention of FIGS. 7-8 and 29.

O-Parameter or P-Parameters of Passivation Coating or Protective Layer

The passivation layer or pH protective coating 34 optionally can have an O-Parameter measured with attenuated total reflection (ATR) of less than 0.4, measured as:

${O\text{-}{Parameter}} = {\frac{{Intensity}\mspace{14mu} {at}\mspace{14mu} 1253\mspace{14mu} {cm}^{- 1}}{{Maximum}\mspace{14mu} {intensity}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {range}\mspace{14mu} 1000\mspace{14mu} {to}\mspace{14mu} 1100\mspace{14mu} {cm}^{- 1}}.}$

The O-Parameter is defined in U.S. Pat. No. 8,067,070, which claims an O-parameter value of most broadly from 0.4 to 0.9. It can be measured from physical analysis of an FTIR amplitude versus wave number plot to find the numerator and denominator of the above expression, as shown in FIG. 25, which is the same as FIG. 5 of U.S. Pat. No. 8,067,070, except annotated to show interpolation of the wave number and absorbance scales to arrive at an absorbance at 1253 cm⁻¹ of 0.0424 and a maximum absorbance at 1000 to 1100 cm⁻¹ of 0.08, resulting in a calculated O-parameter of 0.53. The O-Parameter can also be measured from digital wave number versus absorbance data.

U.S. Pat. No. 8,067,070 asserts that its claimed O-parameter range provides a superior passivation layer or pH protective coating, relying on experiments only with HMDSO and HMDSN, which are both non-cyclic siloxanes. Surprisingly, it has been found by the present inventors that if the PECVD precursor is a cyclic siloxane, for example OMCTS, O-parameters outside the ranges claimed in U.S. Pat. No. 8,067,070, using OMCTS, can provide better results than are obtained in U.S. Pat. No. 8,067,070 with HMDSO.

Alternatively in the embodiment of FIGS. 7-8 and 29, the O-parameter can have a value of from 0.1 to 0.39, or from 0.15 to 0.37, or from 0.17 to 0.35.

Even another aspect of the invention can be a composite material as just described, exemplified in FIGS. 7-8 and 29, wherein the passivation layer or pH protective coating shows an N-Parameter measured with attenuated total reflection (ATR) of less than 0.7, measured as:

${N\text{-}{Parameter}} = {\frac{{Intensity}\mspace{14mu} {at}\mspace{14mu} 840\mspace{14mu} {cm}^{- 1}}{{Intensity}\mspace{14mu} {at}\mspace{14mu} 799\mspace{14mu} {cm}^{- 1}}.}$

The N-Parameter is also described in U.S. Pat. No. 8,067,070, and can be measured analogously to the O-Parameter except that intensities at two specific wave numbers are used neither of these wave numbers is a range. U.S. Pat. No. 8,067,070 claims a passivation layer or pH protective coating with an N-Parameter of 0.7 to 1.6. Again, the present inventors have made better coatings employing a passivation layer or pH protective coating 34 having an N-Parameter lower than 0.7, as described above. Alternatively, the N-parameter can have a value of 0.3 to lower than 0.7, or from 0.4 to 0.6, or from at least 0.53 to lower than 0.7.

Theory of Operation

The inventors offer the following theory of operation of the passivation layer or pH protective coating described here. The invention is not limited by the accuracy of this theory or to the embodiments predictable by use of this theory.

The dissolution rate of the SiO_(x) barrier coating or layer, or of glass, is believed to be dependent on SiO bonding within the layer or glass. Oxygen bonding sites (silanols) are believed to increase the dissolution rate.

It is believed that the OMCTS-based passivation layer or pH protective coating bonds with the silanol sites on the SiO_(x) barrier coating or layer, or glass, to “heal” or passivate the SiO_(x) surface or glass and thus dramatically reduce the dissolution rate. In this hypothesis, the thickness of the OMCTS layer is not the primary means of protection the primary means can be passivation of the SiO_(x) or glass surface. It is contemplated that a passivation layer or pH protective coating as described in this specification can be improved by increasing the crosslink density of the passivation layer or pH protective coating.

Optional Graded Composite Layers

The passivation layer or pH protective coating 34 and lubricity layers of any embodiment of FIGS. 7-8 and 29 can be either separate layers with a sharp transition or a single, graduated layer that transitions between the passivation layer or pH protective coating 34 and the lubricity layer, without a sharp interface between them. Another optional expedient contemplated here, for adjacent layers of SiO_(x) and a passivation layer or pH protective coating, can be a graded composite of SiO_(x) and Si_(w)O_(x)C_(y), or its equivalent SiO_(x)C_(y), as defined in the Definition Section.

A graded composite can be separate layers of a lubricity and/or protective and/or barrier coating or layer or coating with a transition or interface of intermediate composition between them, or separate layers of a lubricity and/or protective and/or hydrophobic layer and SiO_(x) with an intermediate distinct passivation layer or pH protective coating of intermediate composition between them, or a single coating or layer that changes continuously or in steps from a composition of a lubricity and/or protective and/or hydrophobic layer to a composition more like SiO_(x), going through the passivation layer or pH protective coating in a normal direction.

The grade in the graded composite can go in either direction. For example, the composition of SiO_(x) can be applied directly to the substrate and graduate to a composition further from the surface of a passivation layer or pH protective coating, and optionally can further graduate to another type of coating or layer, such as a hydrophobic coating or layer or a lubricity coating or layer. Additionally, in any embodiment an adhesion coating or layer, for example Si_(w)O_(x)C_(y), or its equivalent SiO_(x)C_(y), optionally can be applied directly to the substrate before applying the barrier coating or layer.

A graduated passivation layer or pH protective coating is particularly contemplated if a layer of one composition is better for adhering to the substrate than another, in which case the better-adhering composition can, for example, be applied directly to the substrate. It is contemplated that the more distant portions of the graded passivation layer or pH protective coating can be less compatible with the substrate than the adjacent portions of the graded passivation layer or pH protective coating, since at any point the passivation layer or pH protective coating can be changing gradually in properties, so adjacent portions at nearly the same depth of the passivation layer or pH protective coating have nearly identical composition, and more widely physically separated portions at substantially different depths can have more diverse properties. It is also contemplated that a passivation layer or pH protective coating portion that forms a better barrier against transfer of material to or from the substrate can be directly against the substrate, to prevent the more remote passivation layer or pH protective coating portion that forms a poorer barrier from being contaminated with the material intended to be barred or impeded by the barrier.

The applied coatings or layers, instead of being graded, optionally can have sharp transitions between one layer and the next, without a substantial gradient of composition. Such passivation layer or pH protective coating can be made, for example, by providing the gases to produce a layer as a steady state flow in a non-plasma state, then energizing the system with a brief plasma discharge to form a coating or layer on the substrate. If a subsequent passivation layer or pH protective coating is to be applied, the gases for the previous passivation layer or pH protective coating are cleared out and the gases for the next passivation layer or pH protective coating are applied in a steady-state fashion before energizing the plasma and again forming a distinct layer on the surface of the substrate or its outermost previous passivation layer or pH protective coating, with little if any gradual transition at the interface.

PECVD Apparatus

The present apparatus can be used for plasma modifying a workpiece 12 having a surface to be treated, for example a workpiece having a lumen 18 surrounded by a wall 16 defining a surface 16 to be treated. The present apparatus and method can also be used to treat other types of surfaces, such as the exterior surface of a plunger tip, stopper, piston, or stopper. The apparatus generally includes a plasma generator for providing plasma under conditions effective for plasma modification of the surface 16 of the workpiece 12. The apparatus also includes one or more magnetic field generators, further explained in a later section, (for example, any of 61-78, 86-91, 93, 95, 97, or 99) for providing a magnetic field in at least a portion of the lumen 18, or more broadly in or near the plasma. The magnetic field has a position, orientation, and field strength effective to improve the uniformity of plasma modification of the surface. Optionally, the magnitude of the radial component of the magnetic field is approximately 1000 Gauss as it exits the field with an essentially zero Gauss for the axial component.

The apparatus also includes a support for supporting a workpiece 12 in the apparatus in an operative position.

The low-pressure PECVD process described in U.S. Pat. No. 7,985,188, modified by any arrangement of magnets described or claimed in this specification, can be used to provide the barrier coating or layer, lubricity coating or layer, and/or passivation layer or pH protective coating described in this specification. A brief synopsis of that process follows, with reference to present FIGS. 4-6.

A PECVD apparatus or coating station 60 suitable for the present purpose includes a vessel support 50, an inner electrode defined by the probe 108, an outer electrode 160, and a power supply 162. The pre-assembly 12 seated on the vessel support 50 defines a plasma reaction chamber, which optionally can be a vacuum chamber. Optionally, a source of vacuum 98, a reactant gas source 144, a gas feed (probe 108) or a combination of two or more of these can be supplied.

The PECVD apparatus can be used for atmospheric-pressure PECVD, in which case the plasma reaction chamber defined by the pre-assembly 12 does not need to function as a vacuum chamber.

Referring to FIGS. 4-6, the vessel support 50 comprises a gas inlet port 104 for conveying a gas into the pre-assembly 12 seated on the opening 82. The gas inlet port 104 can have a sliding seal provided for example by at least one O-ring 106, or two O-rings in series, or three O-rings in series, which can seat against a cylindrical probe 108 when the probe 108 is inserted through the gas inlet port 104. The probe 108 can be a gas inlet conduit that extends to a gas delivery port at its distal end 110. The distal end 110 of the illustrated embodiment can be inserted at an appropriate depth in the pre-assembly 12 for providing one or more PECVD reactants and other precursor feed or process gases.

FIG. 6 shows additional optional details of the coating station 60 that are usable, for example, with all the illustrated embodiments. The coating station 60 can also have a main vacuum valve 574 in its vacuum line 576 leading to the pressure sensor 152. A manual bypass valve 578 can be provided in the bypass line 580. A vent valve 582 controls flow at the vent 404.

Flow out of the PECVD gas or precursor source 144 can be controlled by a main reactant gas valve 584 regulating flow through the main reactant feed line 586. One component of the gas source 144 can be the organosilicon liquid reservoir 588, containing the precursor. The contents of the reservoir 588 can be drawn through the organosilicon capillary line 590, which optionally can be provided at a suitable length to provide the desired flow rate. Flow of organosilicon vapor can be controlled by the organosilicon shut-off valve 592. Pressure can be applied to the headspace 614 of the liquid reservoir 588, for example a pressure in the range of 0-15 psi (0 to 78 cm. Hg), from a pressure source 616 such as pressurized air connected to the headspace 614 by a pressure line 618 to establish repeatable organosilicon liquid delivery that is not dependent on atmospheric pressure (and the fluctuations therein). The reservoir 588 can be sealed and the capillary connection 620 can be at the bottom of the reservoir 588 to ensure that only neat organosilicon liquid (not the pressurized gas from the headspace 614) flows through the capillary tube 590. The organosilicon liquid optionally can be heated above ambient temperature, if necessary or desirable to cause the organosilicon liquid to evaporate, forming an organosilicon vapor. To accomplish this heating, the apparatus can advantageously include heated delivery lines from the exit of the precursor reservoir to as close as possible to the gas inlet into the syringe. Preheating can be useful, for example, when feeding OMCTS.

Oxidant gas can be provided from the oxidant gas tank 594 via an oxidant gas feed line 596 controlled by a mass flow controller 598 and provided with an oxidant shut-off valve 600.

Optionally in any embodiment, other precursor, oxidant, and/or carrier gas reservoirs such as 602 can be provided to supply additional materials if needed for a particular deposition process. Each such reservoir such as 602 can have an appropriate feed line 604 and shut-off valve 606.

Referring especially to FIG. 4, the processing station 60 can include an electrode 160 fed by a radio frequency power supply 162 for providing an electric field for generating plasma within the pre-assembly 12 during processing. In this embodiment, the probe 108 can be electrically conductive and can be grounded, thus providing a counter-electrode within the pre-assembly 12. Alternatively, in any embodiment the outer electrode 160 can be grounded and the probe 108 can be directly connected to the power supply 162.

In the embodiment of FIGS. 4-6, the outer electrode 160 can either be generally cylindrical as illustrated in FIGS. 4 and 5 or a generally U-shaped elongated channel. Each illustrated embodiment can have one or more sidewalls, such as 164 and 166, and optionally a top end 168, disposed about the pre-assembly 12 in close proximity.

Optionally in any embodiment, the outer electrode (160) can be made of foraminous material, for example a metal wire mesh material. Alternatively, the outer electrode (160) can be made of continuous material (meaning not perforated, woven, knitted or felted, for example), such as a metal cylinder.

Optionally in any embodiment, the inner electrode (108) extends axially into the lumen (18).

Optionally in any embodiment, the plasma modification of the surface (16) of the workpiece (12) comprises chemical vapor deposition, optionally plasma enhanced chemical vapor deposition (PECVD).

As was previously indicated, the inner electrode (108) optionally can do double duty as a material supply tube (104) for providing gaseous material to the lumen (18). The material supply tube (104) optionally, in any embodiment, has a wall disposed within the lumen (18). Optionally in any embodiment, the wall has perforations (any of 122-142) to pass gaseous material to the lumen (18). See in particular FIGS. 4-5 and 26-28.

Optionally in any embodiment, the perforations (e.g. 122, 122 a, 122 b; 134, 134 a, 134 b, 134 c, 134 d; or 135, 135 a, 135 b) can be distributed axially along the generally cylindrical wall 16, as shown in FIGS. 26-28. The perforations (e.g. 122, 124; 130, 132, 134; or 139, 140) optionally can be distributed circumferentially along the generally cylindrical wall 16, as shown in FIGS. 26-28.

The perforations (any of 122-142) can be distributed as circumferentially spaced series of two or more perforations, the respective series spaced axially along the generally cylindrical wall 16, as shown in FIGS. 26-28. The perforations (any of 122-128 or 135-142) can be distributed as plural circumferentially spaced series of two diametrically opposed perforations per series, the respective series spaced axially along the generally cylindrical wall 16, as shown in FIGS. 26 and 28. The diametrically opposed perforations of a first series (e.g. 122 and 124) can be displaced circumferentially about 90 degrees on the generally cylindrical wall 16 with respect to the diametrically opposed perforations of an adjacent second series (e.g. 126 and 128), as shown in FIG. 26. The diametrically opposed perforations of a first series (e.g. 135 and 136) can be displaced circumferentially about 45 degrees on the generally cylindrical wall 16 with respect to the diametrically opposed perforations of the adjacent second series (e.g. 137 and 138), as shown in FIG. 28. The perforations can be distributed as plural circumferentially spaced series of at least three 120-degree-spaced perforations per series (e.g. 130, 132, and 134), the respective series (e.g. 130, 132, and 134, vs. 130 a, 132 a, and 134 a) spaced axially along the generally cylindrical wall 16, as shown in FIG. 27.

As another option, combinations of these different patterns of perforations, or other patterns known or obvious to those skilled in the art, can be used in a single material supply tube 104.

Application of Barrier Coating or Layer

When carrying out the present method, a barrier coating or layer 30 can be applied directly or indirectly to at least a portion of the internal wall 16 of the barrel 14. In the illustrated embodiment, the barrier coating or layer 30 can be applied while the pre-assembly 12 is capped, though this is not a requirement. The barrier coating or layer 30 can be an SiO_(x) barrier coating or layer applied by plasma enhanced chemical vapor deposition (PECVD), under conditions substantially as described in U.S. Pat. No. 7,985,188. The barrier coating or layer 30 can be applied under conditions effective to maintain communication between the barrel lumen 18 and the dispensing portion lumen 26 via the proximal opening 22 at the end of the applying step.

In any embodiment the barrier coating or layer 30 optionally can be applied through the opening 32.

In any embodiment the barrier coating or layer 30 optionally can be applied by introducing a vapor-phase precursor material through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor material on the internal wall of the barrel.

In any embodiment the precursor material for forming the barrier coating optionally can be any of the precursors described in U.S. Pat. No. 7,985,188 or in this specification for formation of the passivating layer or pH protective coating.

In any embodiment the reactant vapor material optionally can be a precursor material mixture with one or more oxidant gases and a carrier gas in a partial vacuum through the opening and employing chemical vapor deposition to deposit a reaction product of the precursor material mixture on the internal wall of the barrel.

In any embodiment the reactant vapor material optionally can be passed through the opening at sub-atmospheric pressure.

In any embodiment plasma optionally can be generated in the barrel lumen 18 by placing an inner electrode into the barrel lumen 18 through the opening 32, placing an outer electrode outside the barrel 14 and using the electrodes to apply plasma-inducing electromagnetic energy which optionally can be radio frequency energy, in the barrel lumen 18. If a different arrangement is used, the plasma-inducing electromagnetic energy can be microwave energy or other forms of electromagnetic energy.

In any embodiment the electromagnetic energy optionally can be direct current.

In any embodiment the electromagnetic energy optionally can be alternating current. The alternating current optionally can be modulated at frequencies including audio, or microwave, or radio, or a combination of two or more of audio, microwave, or radio.

In any embodiment the electromagnetic energy optionally can be applied across the barrel lumen (18).

Application of Passivation Layer or pH Protective Coating

In any embodiment, in addition to applying a first coating or layer as described above, the method optionally can include applying second or further coating or layer of the same material or a different material. As one example useful in any embodiment, particularly contemplated if the first coating or layer is an SiO_(x) barrier coating or layer, a further coating or layer can be placed directly or indirectly over the barrier coating or layer. One example of such a further coating or layer useful in any embodiment is a passivation layer or pH protective coating 34.

Precursors

The precursor for any of the processes for forming the barrier coating or layer, the passivation layer or pH protective coating, or a lubricity coating or layer can include any of the following precursors.

The precursor can be an organosilicon or related compound. The organosilicon precursor is broadly defined as an organometallic precursor. An organometallic precursor is defined in this specification as comprehending compounds of metal elements from Group III and/or Group IV of the Periodic Table having organic residues, for example hydrocarbon, aminocarbon or oxycarbon residues. Organometallic compounds as presently defined include any precursor having organic moieties bonded to silicon or other Group III/IV metal atoms directly, or optionally bonded through oxygen or nitrogen atoms. The relevant elements of Group III of the Periodic Table are Boron, Aluminum, Gallium, Indium, Thallium, Scandium, Yttrium, and Lanthanum, Aluminum and Boron being preferred. The relevant elements of Group IV of the Periodic Table are Silicon, Germanium, Tin, Lead, Titanium, Zirconium, Hafnium, and Thorium, with Silicon and Tin being preferred. Other volatile organic compounds can also be contemplated. However, organosilicon compounds are preferred for performing present invention.

An organosilicon precursor is contemplated, where an “organosilicon precursor” is defined throughout this specification most broadly as a compound having compound having at least one of the linkages:

which is a tetravalent silicon atom connected to an oxygen atom and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom). Another contemplated structure is a tetravalent silicon atom connected to an NH linkage and an organic carbon atom (an organic carbon atom being a carbon atom bonded to at least one hydrogen atom).

Optionally, the organosilicon precursor can be selected from the group consisting of a linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane, a linear silazane, a monocyclic silazane, a polycyclic silazane, a polysilsesquiazane, and a combination of any two or more of these precursors. Also contemplated as a precursor, though not within the two formulas immediately above, can be an alkyl trimethoxysilane.

If an oxygen-containing precursor (for example a siloxane) is used, a representative predicted empirical composition resulting from PECVD under conditions forming a hydrophobic or lubricating passivation layer or pH protective coating would be Si_(w)O_(x)C_(y)H_(z) or its equivalent SiO_(x)C_(y) as defined in the Definition Section, while a representative predicted empirical composition resulting from PECVD under conditions forming a barrier coating or layer would be SiO_(x), where x in this formula is from about 1.5 to about 2.9. If a nitrogen-containing precursor (for example a silazane) is used, the predicted composition would be Si_(w)*N_(x)*C_(y)*H_(z)*, i.e. in Si_(w)O_(x)C_(y)H_(z) or its equivalent SiO_(x)C_(y) as specified in the Definition Section, O is replaced by N and the indices for H are adapted to the higher valency of N as compared to O (3 instead of 2). The latter adaptation will generally follow the ratio of w, x, y and z in a siloxane to the corresponding indices in its silazane counterpart. In a particular aspect of the invention, Si_(w)*N_(x)*C_(y)*H_(z)*(or its equivalent SiN_(x)*C_(y)*) in which w*, x*, y*, and z* are defined the same as w, x, y, and z for the siloxane counterparts, but for an optional deviation in the number of hydrogen atoms.

One type of precursor starting material having the above empirical formula can be a linear siloxane, for example a material having the following formula:

in which each R can be independently selected from alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others, and n can be 1, 2, 3, 4, or greater, optionally two or greater. Several examples of contemplated linear siloxanes are

hexamethyldisiloxane (HMDSO) (particularly for forming the barrier coating or layer 30 of a vessel),

octamethyltrisiloxane,

decamethyltetrasiloxane,

dodecamethylpentasiloxane,

or combinations of two or more of these. The analogous silazanes in which—NH— can be substituted for the oxygen atom in the above structure are also useful for making analogous passivation layers or pH protective coatings or layers. Several examples of contemplated linear silazanes are octamethyltrisilazane, decamethyltetrasilazane, or combinations of two or more of these.

Another type of precursor starting material, among the preferred starting materials in the present context, can be a monocyclic siloxane, for example a material having the following structural formula:

in which R can be defined as for the linear structure and “a” can be from 3 to about 10, or the analogous monocyclic silazanes. Several examples of contemplated hetero-substituted and unsubstituted monocyclic siloxanes and silazanes include:

-   -   1,3,5-trimethyl-1,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane     -   2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,     -   pentamethylcyclopentasiloxane,     -   pentavinylpentamethylcyclopentasiloxane,     -   hexamethylcyclotrisiloxane,     -   hexaphenylcyclotrisiloxane (HMCTS),     -   octamethylcyclotetrasiloxane (OMCTS),     -   decamethylcyclopentasiloxane (DMCPS),     -   2,2,4,4,6,6,8,8-octamethyl-1,5-dimethano-3,7-dioxa-2,4,6,8-tetrasiloxane,     -   octaphenylcyclotetrasiloxane,     -   decamethylcyclopentasiloxane,     -   dodecamethylcyclohexasiloxane,     -   methyl(3,3,3-trifluoropropl)cyclosiloxane,     -   Cyclic organosilazanes are also contemplated, such as     -   Octamethylcyclotetrasilazane,     -   1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasilazane,     -   hexamethylcyclotrisilazane,     -   octamethylcyclotetrasilazane,     -   decamethylcyclopentasilazane,     -   dodecamethylcyclohexasilazane, or     -   combinations of any two or more of these.

Another type of precursor starting material, among the preferred starting materials in the present context, can be a polycyclic siloxane, for example a material having one of the following structural formulas:

in which Y can be oxygen or nitrogen, E is silicon, and Z is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others. When each Y is oxygen, the respective structures, from left to right, are a Silatrane, a Silquasilatrane, and a Silproatrane. When Y is nitrogen, the respective structures are an azasilatrane, an azasilquasiatrane, and an azasilproatrane.

Another type of polycyclic siloxane precursor starting material, among the preferred starting materials in the present context, can be a polysilsesquioxane, with the empirical formula RSiO1.5 and the structural formula:

in which each R is a hydrogen atom or an organic substituent, for example alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl, alkyne, or others. Two commercial materials of this sort are SST-eM01 poly(methylsilsesquioxane), in which each R can be methyl, and SST-3MH_(1.1) poly(Methyl-Hydridosilsesquioxane), in which 90% of the R groups are methyl, 10% are hydrogen atoms. This material is available in a 10% solution in tetrahydrofuran, for example. Combinations of two or more of these are also contemplated. Other examples of a contemplated precursor are methylsilatrane, CAS No. 2288-13-3, in which each Y is oxygen and Z is methyl, methylazasilatrane, poly(methylsilsesquioxane) (for example SST-eM01 poly(methylsilsesquioxane)), in which each R optionally can be methyl, SST-3MH_(1.1) poly(Methyl-Hydridosilsesquioxane) (for example SST-3MH_(1.1) poly(Methyl-Hydridosilsesquioxane)), in which 90% of the R groups are methyl and 10% are hydrogen atoms, or a combination of any two or more of these.

The analogous polysilsesquiazanes in which —NH— can be substituted for the oxygen atom in the above structure are also useful for making analogous passivation layer or pH protective coating. Examples of contemplated polysilsesquiazanes are a poly(methylsilsesquiazane), in which each R can be methyl, and a poly(Methyl-Hydridosilsesquiazane, in which 90% of the R groups are methyl, 10% are hydrogen atoms. Combinations of two or more of these are also contemplated.

One particularly contemplated precursor for the barrier coating or layer according to the present invention can be a linear siloxane, for example hexamethyldisiloxane or HMDSO. One particularly contemplated precursor for the lubricity coating or layer and the passivation layer or pH protective coating according to the present invention can be a cyclic siloxane, for example octamethylcyclotetrasiloxane (OMCTS).

It is believed that the OMCTS or other cyclic siloxane molecule provides several advantages over other siloxane materials. First, its ring structure is believed to result in a less dense passivation layer or pH protective coating (as compared to passivation layer or pH protective coating prepared from HMDSO). The molecule also is believed to allow selective ionization so that the final structure and chemical composition of the passivation layer or pH protective coating can be directly controlled through the application of the plasma power. Other organosilicon molecules are readily ionized (fractured) so that it can be more difficult to retain the original structure of the molecule.

Another example of a suitable precursor is a fluorinated precursor for a fluorinated polymer layer.

The fluorinated polymer can be deposited directly or with intervening layers on the sliding surface of a plunger tip, piston, stopper, or seal 36, the internal wall 16, or both. The fluorinated polymer optionally is applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface.

Optionally, the precursor comprises:

-   -   dimeric tetrafluoroparaxylylene,     -   difluorocarbene,     -   monomeric tetrafluoroethylene,     -   oligomeric tetrafluoroethylene having the formula         F₂C═CF(CF₂)_(x)F in which x is from 1 to 100, optionally 2 to         50, optionally 2-20, optionally 2-10,     -   sodium chlorodifluoroacetate,     -   chlorodifluoromethane,     -   bromodifluoromethane,     -   hexafluoropropylene oxide,     -   1 H,1 H,2H,2H-perfluorodecyl acrylate (FDA),     -   a bromofluoroalkane in which the alkane moiety has from 1 to 6         carbon atoms,     -   an iodofluoroalkane in which the alkane moiety has from 1 to 6         carbon atoms, or     -   a combination of any two or more of these.

The fluorinated polymer is:

-   -   optionally from at least 0.01 micrometer to at most 100         micrometers thick,     -   optionally from at least 0.05 micrometers to at most 90         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 80         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 70         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 60         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 50         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 40         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 30         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 20         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 15         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 12         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 10         micrometers thick     -   optionally from at least 0.1 micrometers to at most 8         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 6         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 4         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 2         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 1         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.9         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.8         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.7         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.6         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.5         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 5         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 4         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 3         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 2         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 1 micrometer         thick,     -   optionally about 10 micrometers thick,     -   optionally about 2 micrometers thick.

The fluorinated polymer optionally can be applied by vapor deposition, for example chemical vapor deposition. Optionally, the fluorinated polymer can be applied by chemical vapor deposition of dimeric tetrafluoroparaxylylene. An example of a suitable fluorinated polymer is polytetrafluoroparaxylylene. Optionally, the fluorinated polymer consists essentially of polytetrafluoroparaxylylene.

Optionally in any embodiment, the fluorinated polymer coating or layer comprises polytetrafluoroethylene. Optionally in any embodiment, the fluorinated polymer coating or layer consists essentially of polytetrafluoroethylene.

For example, in any embodiment, the fluorinated polymer coating or layer can be applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface, to produce the fluorinated polymer coating or layer on the fluid receiving interior surface. Optionally in any embodiment, the fluorinated polymer coating or layer is applied by chemical vapor deposition. For one example, in any embodiment, the fluorinated polymer coating or layer can be applied by heated wire chemical vapor deposition (HWCVD). For another example, in any embodiment, the fluorinated polymer coating or layer can be applied by plasma enhanced chemical vapor deposition (PECVD). Mixed processes or other processes for applying a suitable coating are also contemplated, in any embodiment.

Another example of a suitable HWCVD process for applying the fluorinated polymer coating is the process described in Hilton G. Pryce Lewis, Neeta P. Bansal, Aleksandr J. White, Erik S. Handy, HWCVD of Polymers: Commercialization and Scale-up, THIN SOLID FILMS 517 (2009) 3551-3554; and US Publ. Appl. 2012/0003497 A1, published Jan. 5, 2012, which are incorporated here by reference in their entirety for their description of fluorinated polymer coatings and their application.

Optionally in any embodiment, the precursor comprises Parylene N or poly(paraxylylene); Parylene C or poly(2-chloroparaxylylene); Parylene D or poly(2,5-dichloropara-xylylene); Parylene HT® or poly(tetrafluoropara-xylylene), or their dimers, or a combination of two or more of these. Parylenes can be applied to a substrate as described by Specialty Coating Systems, Inc., discussed for example in Lonny Wolgemuth, Challenges With Prefilled Syringes: The Parylene Solution, www.ongrugdelivery.com, pp. 44-45 (Frederick Furness Publishing, 2012). The documents mentioned in this paragraph are incorporated by reference here.

In any of the PECVD methods according to the present invention, the applying step optionally can be carried out by vaporizing the precursor and providing it in the vicinity of the substrate. For example, OMCTS can be vaporized by heating it to about 50° C. before applying it to the PECVD apparatus.

The organosilicon precursor can be delivered at a rate of equal to or less than 10 sccm, optionally equal to or less than 6 sccm, optionally equal to or less than 2.5 sccm, optionally equal to or less than 1.5 sccm, optionally equal to or less than 1.25 sccm. Larger pharmaceutical packages or other vessels or other changes in conditions or scale may require more or less of the precursor.

Ratios of Components For Passivation Layer or pH Protective Coating

Generally, for a passivation layer or pH protective coating, O₂ can be present in an amount (which can, for example be expressed by the flow rate in sccm) which can be less than one order of magnitude greater than the organosilicon amount. In contrast, in order to achieve a barrier coating or layer, the amount of O₂ typically can be at least one order of magnitude higher than the amount of organosilicon precursor.

As some specific examples of suitable proportions of the respective constituents, the volume ratio (in sccm) of organosilicon precursor to O₂ for a passivation layer or pH protective coating can be in the range from 0.1:1 to 10:1, optionally in the range from 0.3:1 to 8:1, optionally in the range from 0.5:1 to 5:1, optionally from 1:1 to 3:1. Some non-exhaustive alternative selections and suitable proportions of the precursor gas, oxygen, and a carrier gas are provided below.

The process gas can contain this ratio of gases for preparing a lubricity and/or passivation layer or pH protective coating:

-   -   from 0.5 to 10 standard volumes of the precursor;     -   from 1 to 100 standard volumes of a carrier gas,     -   from 0.1 to 10 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 1 to 80 standard volumes of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes, of the precursor;     -   from 1 to 100 standard volumes of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 3 to 70 standard volumes, of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes, of the precursor;     -   from 3 to 70 standard volumes of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 1 to 100 standard volumes of a carrier gas,     -   from 0.2 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes, of the precursor;     -   from 1 to 100 standard volumes of a carrier gas,     -   from 0.2 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 3 to 70 standard volumes of a carrier gas,     -   from 0.2 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes of the precursor;     -   from 3 to 70 standard volumes of a carrier gas,     -   from 0.2 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 1 to 100 standard volumes of a carrier gas,     -   from 0.2 to 1 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes of the precursor;     -   from 1 to 100 standard volumes of a carrier gas,     -   from 0.2 to 1 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 3 to 70 standard volumes of a carrier gas,     -   from 0.2 to 1 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   2 to 4 standard volumes, of the precursor;     -   from 3 to 70 standard volumes of a carrier gas,     -   from 0.2 to 1 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 5 to 100 standard volumes of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes, of the precursor;     -   from 5 to 100 standard volumes of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 10 to 70 standard volumes, of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes, of the precursor;     -   from 10 to 70 standard volumes of a carrier gas,     -   from 0.1 to 2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 5 to 100 standard volumes of a carrier gas,     -   from 0.5 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes, of the precursor;     -   from 5 to 100 standard volumes of a carrier gas,     -   from 0.5 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 10 to 70 standard volumes, of a carrier gas,     -   from 0.5 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes of the precursor;     -   from 10 to 70 standard volumes of a carrier gas,     -   from 0.5 to 1.5 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 5 to 100 standard volumes of a carrier gas,     -   from 0.8 to 1.2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 2 to 4 standard volumes of the precursor;     -   from 5 to 100 standard volumes of a carrier gas,     -   from 0.8 to 1.2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   from 1 to 6 standard volumes of the precursor;     -   from 10 to 70 standard volumes of a carrier gas,     -   from 0.8 to 1.2 standard volumes of an oxidizing agent.

-   alternatively this ratio:     -   2 to 4 standard volumes, of the precursor;     -   from 10 to 70 standard volumes of a carrier gas,     -   from 0.8 to 1.2 standard volumes of an oxidizing agent.

Exemplary reaction conditions for preparing a passivation layer or pH protective coating according to the present invention in a 3 ml sample size syringe with a ⅛″ diameter tube (open at the end) are as follows:

-   Flow rate ranges: -   OMCTS: 0.5-10 sccm -   Oxygen: 0.1-10 sccm -   Argon: 1.0-200 sccm -   Power: 0.1-500 watts

In another contemplated embodiment the proportions of precursor, oxygen, and Argon can be, for example:

-   OMCTS: 0.5-5.0 sccm -   Oxygen: 0.1-5.0 sccm -   Argon: 1.0-20 sccm

In yet another contemplated embodiment the proportions of precursor, oxygen, and Argon and the power level can be, for example:

-   Specific Flow rates: -   OMCTS: 2.0 sccm -   Oxygen: 0.7 sccm -   Argon: 7.0 sccm -   Power: 3.5 watts

The coatings can vary from the above proportions, however. For example, to provide a coating with lubricity which also serves as a passivation layer or pH protection coating, the following proportions of gases can be used:

(A) from 0.5 to 10 standard volumes, optionally from 1 to 6 standard volumes, optionally from 2 to 4 standard volumes, optionally equal to or less than 6 standard volumes, optionally equal to or less than 2.5 standard volumes, optionally equal to or less than 1.5 standard volumes, optionally equal to or less than 1.25 standard volumes of the precursor, for example OMCTS or one of the other precursors of any embodiment;

(B) from 0 to 100 standard volumes, optionally from 1 to 80 standard volumes, optionally from 5 to 100 standard volumes, optionally from 10 to 70 standard volumes, of a carrier gas of any embodiment;

(C) from 0.1 to 10 standard volumes, optionally from 0.1 to 2 standard volumes, optionally from 0.2 to 1.5 standard volumes, optionally from 0.2 to 1 standard volumes, optionally from 0.5 to 1.5 standard volumes, optionally from 0.8 to 1.2 standard volumes of an oxidizing agent.

The presence of the precursor and O₂ in the volume ratios as given in the working examples can be specifically suitable to achieve a passivation layer or pH protective coating.

In one aspect of the invention, a diluent or carrier gas can be absent in the reaction mixture; in another aspect of the invention, it can be present. Suitable carrier gases include any noble gas, for example Argon, Helium, Neon, Xenon or combinations of two or more of these. When the carrier gas is present in the reaction mixture, it is typically present in a volume (in sccm) exceeding the volume of the organosilicon precursor. For example, the ratio of the organosilicon precursor to carrier gas can be from 1:1 to 1:50, optionally from 1:5 to 1:40, optionally from 1:10 to 1:30. One function of the carrier gas can be to dilute the reactants in the plasma, encouraging the formation of a coating on the substrate instead of powdered reaction products that do not adhere to the substrate and are largely removed with the exhaust gases.

The addition of Argon gas has been found to improve the performance of the passivation layer or pH protective coating 34. It is believed that additional ionization of the molecule in the presence of Argon contributes to this performance. The Si—O—Si bonds of the molecule have a high bond energy followed by the Si—C, with the C—H bonds being the weakest. Passivation or pH protection appear to be achieved when a portion of the C—H bonds are broken. This allows the connecting (cross-linking) of the structure as it grows. Addition of oxygen (with the Argon) is understood to enhance this process. A small amount of oxygen can also provide C—O bonding to which other molecules can bond. The combination of breaking C—H bonds and adding oxygen all at low pressure and power leads to a chemical structure that can be solid while providing passivation or pH protection.

In any of the disclosed embodiments, one preferred combination of process gases includes octamethylcyclotetrasiloxane (OMCTS) or another cyclic siloxane as the precursor; O_(2,) nitrous oxide (N₂O), ozone (O₃), water vapor (which can decompose in the plasma to yield oxygen) or another oxidizing gas, which means any other gas that oxidizes the precursor during PECVD at the conditions employed, preferably O₂; and a carrier gas, for example a noble carrier gas, for example helium, argon, krypton, xenon, neon, or a combination of two or more of these. Helium and argon are particularly contemplated.

The gaseous reactant or process gas can be at least substantially free of nitrogen. This combination is contemplated to improve the resulting passivation layer or pH protective coating.

Application Method

A passivation layer or pH protective coating 34 optionally can be applied directly or indirectly over the barrier coating or layer 30, and optionally can be applied to a pre-assembly such as 12 while the pre-assembly is capped, under conditions effective to maintain communication between the barrel lumen 18 and the dispensing portion lumen 26 via the proximal opening 22 at the end of applying the passivation layer or pH protective coating 34.

Vessel Made Of Glass

Optionally in any embodiment, the passivation layer or pH protective coating 34 can be applied as the first or sole vapor-deposited coating or layer 30, instead of or in addition to its application as a further layer. This expedient may be useful, for example, where the barrel is made of glass. The presently disclosed passivation layer or pH protective coating also can reduce the dissolution of glass by contents having the pH values indicated as attacking SiO_(x) coatings or layers.

A pharmaceutical package 210 is contemplated as shown in any embodiment, for example FIGS. 7-8 and 29, comprising a vessel or vessel part made of glass; optionally a barrier coating or layer or layer such as 30 on the vessel or vessel part; a passivation layer or pH protective coating such as 34 on the vessel, vessel part, or barrier coating or layer or layer; and a pharmaceutical composition or preparation contained within the vessel.

In this glass embodiment the barrier coating or layer or layer can be optional because a glass vessel wall in itself is an extremely good barrier coating or layer. It is contemplated to optionally provide a barrier coating or layer primarily to provide isolation: in other words, to prevent contact and interchange of material of any kind, such as ions of the glass or constituents of the pharmaceutical composition or preparation between the vessel wall and the contents of the vessel. The protective layer as defined in this specification can be contemplated to perform the isolation function independently, at least to a degree. This passivation coating or pH protection layer can be contemplated to provide a useful function on glass in contact with the pharmaceutical composition or preparation, as the present working examples show that borosilicate glass, commonly used today for pharmaceutical packaging, can be dissolved by a fluid composition having a pH exceeding 5. Particularly in applications where such dissolution can be disadvantageous or perceived to be disadvantageous, the present passivation layers or protective coatings or layers will find utility.

The vessel can be made, for example of glass of any type used in medical or laboratory applications, such as soda-lime glass, borosilicate glass, or other glass formulations. One function of a passivation layer or pH protective coating on a glass vessel can be to reduce the ingress of ions in the glass, either intentionally or as impurities, for example sodium, calcium, or others, from the glass to the contents of the pharmaceutical package or other vessel, such as a reagent or blood in an evacuated blood collection tube. Alternatively, a dual functional protective/lubricity coating or layer can be used on a glass vessel in whole or in part, such as selectively at surfaces contacted in sliding relation to other parts, to provide lubricity, for example to ease the insertion or removal of a stopper or passage of a sliding element such as a piston in a syringe, as well as to provide the isolation of a passivation layer or pH protective coating. Still another reason to coat a glass vessel, for example with a dual functional hydrophobic and passivation layer or pH protective coating, can be to prevent a reagent or intended sample for the pharmaceutical package or other vessel, such as blood, from sticking to the wall of the vessel or an increase in the rate of coagulation of the blood in contact with the wall of the vessel, as well as to provide the isolation of a passivation layer or pH protective coating.

A related embodiment can be a vessel as described in the previous paragraphs, in which the barrier coating or layer or layer can be made of soda lime glass, borosilicate glass, or another type of glass coating or layer on a substrate.

Plasma Conditions for Passivation Layer or pH Protective Coating

The precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes powered at radio frequency, optionally a frequency of 10 kHz to 2.45 GHz, optionally from 10 kHz to less than 300 MHz, optionally from 1 to 50 MHz, optionally from 10 to 15 MHz, alternatively from about 13 to about 14 MHz, optionally at or about 13.56 MHz. Typically, the plasma in the PECVD process can be generated at RF frequency, although microwave or other electromagnetic energy can also be used. For providing a protective layer on the interior of a vessel by a plasma reaction carried out within the vessel, the plasma of any embodiment can be generated with an electric power of from 0.1 to 500 W, optionally from 0.1 to 400 W, optionally from 0.1 to 300 W, optionally from 1 to 250 W, optionally from 1 to 200 W, even optionally from 10 to 150 W, optionally from 20 to 150 W, for example of 40 W, optionally from 40 to 150 W, even optionally from 60 to 150 W.

For any PECVD process in any embodiment herein, PECVD can be initiated by applying an initial higher power level within the stated range, followed by a subsequent lower power level within the stated range. The initial higher power level can be applied, for example, for from 1 to 3 seconds. The subsequent lower power level can be applied, for example, for the remainder of PECVD.

For forming a coating intended to provide lubricity in addition to passivation or pH protection, the precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power at from 0.1 to 25 W, optionally from 1 to 22 W, optionally from 1 to 10 W, even optionally from 1 to 5 W, optionally from 2 to 4 W, for example of 3 W, optionally from 3 to 17 W, even optionally from 5 to 14 W, for example 6 or 7.5 W, optionally from 7 to 11 W, for example of 8 W.

The ratio of the electrode power to the plasma volume can be less than 100 W/ml, optionally can be from 0.1 to 100 W/mL, optionally can be from 5 W/ml to 75 W/ml, optionally can be from 6 W/ml to 60 W/ml, optionally can be from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml. These power levels are suitable for applying passivation layers or protective coatings or layers to syringes and sample tubes and pharmaceutical packages or other vessels of similar geometry having a void volume of 5 mL in which PECVD plasma can be generated. It is contemplated that for larger or smaller objects the power applied, in Watts, should be increased or reduced accordingly to scale the process to the size of the substrate.

For forming a coating intended to provide lubricity in addition to passivation or pH protection, the precursor can be contacted with a plasma made by energizing the vicinity of the precursor with electrodes supplied with electric power density at less than 10 W/ml of plasma volume, alternatively from 6 W/ml to 0.1 W/ml of plasma volume, alternatively from 5 W/ml to 0.1 W/ml of plasma volume, alternatively from 4 W/ml to 0.1 W/ml of plasma volume, alternatively from 2 W/ml to 0.2 W/ml of plasma volume, alternatively from 10 W/ml to 50 W/ml, optionally from 20 W/ml to 40 W/ml.

Optionally, in any embodiment of FIGS. 7-8 and 29 the passivation layer or pH protective coating can be applied by PECVD at a power level per of more than 22,000 kJ/kg of mass of precursor, or more than 30,000 kJ/kg of mass of precursor, or more than 40,000 kJ/kg of mass of precursor, or more than 50,000 kJ/kg of mass of precursor, or more than 60,000 kJ/kg of mass of precursor, or more than 62,000 kJ/kg of mass of precursor, or more than 70,000 kJ/kg of mass of precursor, or more than 80,000 kJ/kg of mass of precursor, or more than 100,000 kJ/kg of mass of precursor, or more than 200,000 kJ/kg of mass of precursor, or more than 300,000 kJ/kg of mass of precursor, or more than 400,000 kJ/kg of mass of precursor, or more than 500,000 kJ/kg of mass of precursor.

Optionally, in any embodiment of FIGS. 7-8 and 29 the passivation layer or pH protective coating 34 can be applied by PECVD at a power level per of less than 2,000,000 kJ/kg of mass of precursor, or less than1,000,000 kJ/kg of mass of precursor, or less than 700,000 kJ/kg of mass of precursor, or less than 500,000 kJ/kg of mass of precursor, or less than 100,000 kJ/kg of mass of precursor, or less than 90,000 kJ/kg of mass of precursor, or less than 81,000 kJ/kg of mass of precursor.

For a PECVD process the deposition time can be from 1 to 30 sec, alternatively from 2 to 10 sec, alternatively from 3 to 9 sec. The purposes for optionally limiting deposition time can be to avoid overheating the substrate, to increase the rate of production, and to reduce the use of process gas and its constituents. The purposes for optionally extending deposition time can be to provide a thicker passivation layer or pH protective coating for particular deposition conditions.

Other methods can be used to apply the passivation layer or pH protective coating. For example, hexamethylene disilazane (HMDZ) can be used as the precursor. HMDZ has the advantage of containing no oxygen in its molecular structure. This passivation layer or pH protective coating treatment is contemplated to be a surface treatment of the SiO_(x) barrier coating or layer with HMDZ. It is contemplated that HMDZ will react with the —OH sites that are present in the silicon dioxide coating, resulting in the evolution of NH3 and bonding of S—(CH₃)₃ to the silicon (it is contemplated that hydrogen atoms will be evolved and bond with nitrogen from the HMDZ to produce NH3).

It is contemplated that this HMDZ passivation layer or pH protective coating can be accomplished through several possible paths.

One contemplated path can be dehydration/vaporization of the HMDZ at ambient temperature. First, an SiO_(x) surface can be deposited, for example using hexamethylene disiloxane (HMDSO). The as-coated silicon dioxide surface then can be reacted with HMDZ vapor. In an embodiment, as soon as the SiO_(x) surface is deposited onto the article of interest, the vacuum can be maintained. The HMDSO and oxygen are pumped away and a base vacuum is achieved. Once base vacuum is achieved, HMDZ vapor can be flowed over the surface of the silicon dioxide (as coated on the part of interest) at pressures from the mTorr range to many Torr. The HMDZ then can be pumped away (with the resulting NH₃ that is a by-product of the reaction). The amount of NH₃ in the gas stream can be monitored (with a residual gas analyzer—RGA—as an example) and when there is no more NH₃ detected, the reaction is complete. The part then can be vented to atmosphere (with a clean dry gas or nitrogen). The resulting surface then can be found to have been passivated or protected. It is contemplated that this method optionally can be accomplished without forming a plasma.

Alternatively, after formation of the SiO_(x) barrier coating or layer, the vacuum can be broken before dehydration/vaporization of the HMDZ. Dehydration/vaporization of the HMDZ can then be carried out in either the same apparatus used for formation of the SiO_(x) barrier coating or layer or different apparatus.

Dehydration/vaporization of HMDZ at an elevated temperature is also contemplated. The above process can alternatively be carried out at an elevated temperature exceeding room temperature up to about 150° C. The maximum temperature can be determined by the material from which the coated part is constructed. An upper temperature should be selected that will not distort or otherwise damage the part being coated.

Dehydration/vaporization of HMDZ with a plasma assist is also contemplated. After carrying out any of the above embodiments of dehydration/vaporization, once the HMDZ vapor is admitted into the part, plasma can be generated. The plasma power can range from a few watts to 100+ watts (similar powers as used to deposit the SiO_(x)). The above is not limited to HMDZ and could be applicable to any molecule that will react with hydrogen, for example any of the nitrogen-containing precursors described in this specification.

Surprisingly, it has been found that the above stated coatings or layers can be applied to the capped pre-assembly 12 with substantially no deposition of the vapor-deposited coating 30 in the dispensing portion lumen 26.

In certain embodiments, the generation of uniform plasma throughout the portion of the vessel to be coated is contemplated, as it has been found in certain instances to generate a better passivation layer or pH protective coating. Uniform plasma means regular plasma that does not include a substantial amount of hollow cathode plasma (which has higher emission intensity than regular plasma and can be manifested as a localized area of higher intensity interrupting the more uniform intensity of the regular plasma).

It is further contemplated that any embodiment of the passivation layer or pH protective coating processes described in this specification can also be carried out without using the article to be coated to contain the plasma. For example, external surfaces of medical devices, for example catheters, surgical instruments, closures, and others can be passivated or protected.

Non-Organosilicon Passivation Layer or pH Protective Coating

Another way of applying the passivation layer or pH protective coating can be to apply as the passivation layer or pH protective coating an amorphous carbon or fluorinated polymer coating, or a combination of the two.

Amorphous carbon coatings can be formed by PECVD using a saturated hydrocarbon, (e.g. methane, ethane, ethylene or propane), or an unsaturated hydrocarbon (e.g. ethylene, acetylene), or a combination of two or more of these as a precursor for plasma polymerization.

Fluorinated polymer coatings can be applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface.

Optionally, the precursor comprises:

-   -   dimeric tetrafluoroparaxylylene,     -   difluorocarbene,     -   monomeric tetrafluoroethylene,     -   oligomeric tetrafluoroethylene having the formula F2C═CF(CF2)xF         in which x can be from 1 to 100, optionally 2 to 50, optionally         2-20, optionally 2-10,     -   sodium chlorodifluoroacetate,     -   chlorodifluoromethane,     -   bromodifluoromethane,     -   hexafluoropropylene oxide,     -   1 H,1 H,2H,2H-perfluorodecyl acrylate (FDA),     -   a bromofluoroalkane in which the alkane moiety can have from 1         to 6 carbon atoms,     -   an iodofluoroalkane in which the alkane moiety can have from 1         to 6 carbon atoms, or     -   a combination of any two or more of these.

The fluorinated polymer is:

-   -   optionally from at least 0.01 micrometer to at most 100         micrometers thick,     -   optionally from at least 0.05 micrometers to at most 90         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 80         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 70         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 60         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 50         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 40         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 30         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 20         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 15         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 12         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 10         micrometers thick     -   optionally from at least 0.1 micrometers to at most 8         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 6         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 4         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 2         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 1         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.9         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.8         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.7         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.6         micrometers thick,     -   optionally from at least 0.1 micrometers to at most 0.5         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 5         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 4         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 3         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 2         micrometers thick,     -   optionally from at least 0.5 micrometers to at most 1 micrometer         thick,     -   optionally about 10 micrometers thick,     -   optionally about 2 micrometers thick.

The fluorinated polymer optionally can be applied by vapor deposition, for example chemical vapor deposition. Optionally, the fluorinated polymer can be applied by chemical vapor deposition of dimeric tetrafluoroparaxylylene. An example of a suitable fluorinated polymer can be polytetrafluoroparaxylylene. Optionally, the fluorinated polymer consists essentially of polytetrafluoroparaxylylene.

Optionally in any embodiment, the fluorinated polymer coating or layer comprises polytetrafluoroethylene. Optionally in any embodiment, the fluorinated polymer coating or layer consists essentially of polytetrafluoroethylene.

For example, in any embodiment, the fluorinated polymer coating or layer can be applied by chemically modifying a precursor, while on or in the vicinity of the fluid receiving interior surface, to produce the fluorinated polymer coating or layer on the fluid receiving interior surface. Optionally in any embodiment, the fluorinated polymer coating or layer can be applied by chemical vapor deposition. For one example, in any embodiment, the fluorinated polymer coating or layer can be applied by heated wire chemical vapor deposition (HWCVD). For another example, in any embodiment, the fluorinated polymer coating or layer can be applied by plasma enhanced chemical vapor deposition (PECVD). Mixed processes or other processes for applying a suitable coating are also contemplated, in any embodiment.

Another example of a suitable HWCVD process for applying the fluorinated polymer coating can be the process described in Hilton G. Pryce Lewis, Neeta P. Bansal, Aleksandr J. White, Erik S. Handy, HWCVD of Polymers: Commercialization and Scale-up, THIN SOLID FILMS 517 2009) 3551-3554; US Publ. Appl. 2012/0003497 A1, published Jan. 5, 2012; and US Publ. Appl. 2011/0186537, published Aug. 4, 2011, which are incorporated here by reference in their entirety for their description of fluorinated polymer coatings and their application.

It is contemplated that that amorphous carbon and/or fluorinated polymer coatings will provide better passivation or protection of an SiO_(x) barrier coating or layer than a siloxane coating since an amorphous carbon and/or fluorinated polymer coating will not contain silanol bonds.

It is further contemplated that fluorosilicon precursors can be used to provide a passivation layer or pH protective coating over an SiO_(x) barrier coating or layer. This can be carried out by using as a precursor a fluorinated silane precursor such as hexafluorosilane and a PECVD process. The resulting coating would also be expected to be a non-wetting coating.

Liquid-Applied Passivation Layer or pH Protective Coating

Another example of a suitable barrier or other type of passivation layer or pH protective coating, usable in conjunction with the PECVD-applied passivation layer or pH protective coating or other PECVD treatment as disclosed here, can be a liquid barrier, lubricant, surface energy tailoring, or passivation layer or pH protective coating 90 applied to the inner or interior surface of a pharmaceutical package or other vessel, either directly or with one or more intervening PECVD-applied coatings or layers described in this specification, for example SiO_(x), a lubricity coating or layer and/or a passivation layer or pH protective coating, or both.

A suitable liquid barrier, lubricity, or passivation layer or pH protective coating 90 also optionally can be applied, for example, by applying a liquid monomer or other polymerizable or curable material to the inner or interior surface of the vessel 80 and curing, polymerizing, or crosslinking the liquid monomer to form a solid polymer, or by applying a solvent-dispersed polymer to the surface 88 and removing the solvent.

Any of the above methods can include as a step forming a passivation layer or pH protective coating on the interior of a vessel via the vessel port at a processing station or device. One example can be applying a liquid passivation layer or pH protective coating, for example of a curable monomer, prepolymer, or polymer dispersion, to the inner or interior surface of a vessel and curing it to form a film that physically isolates the contents of the vessel from its inner or interior surface 88. The prior art describes polymer passivation layer or pH protective coating technology as suitable for treating plastic blood collection tubes. For example, the acrylic and polyvinylidene chloride (PVdC) passivation layer or pH protective coating materials and methods described in U.S. Pat. No. 6,165,566, which is hereby incorporated by reference, optionally can be used.

Any of the above methods can also include as a step forming a coating or layer on the exterior outer wall of a vessel 80. The exterior coating or layer optionally can be a barrier coating or layer or layer, optionally an oxygen barrier coating or layer or layer, or optionally a water barrier coating or layer or layer. The exterior coating or layer can also be an armor layer that protects the outer wall of a vessel 80. One example of a suitable exterior coating or layer can be polyvinylidene chloride, which functions both as a water barrier and an oxygen barrier. Optionally, the exterior coating or layer can be applied as a water-based coating or layer. The exterior coating or layer optionally can be applied by dipping the vessel in it, spraying it on the pharmaceutical package or other vessel, or other expedients.

Yet another coating modality contemplated for protecting or passivating an SiO_(x) barrier coating or layer can be coating the barrier coating or layer using a polyamidoamine epichlorohydrin resin. For example, the barrier coating or layer can be applied by dip coating in a fluid polyamidoamine epichlorohydrin resin melt, solution or dispersion and cured by autoclaving or other heating at a temperature between 60 and 100° C.

It is contemplated that a coating of polyamidoamine epichlorohydrin resin can be preferentially used in aqueous environments between pH 5-8, as such resins are known to provide high wet strength in paper in that pH range. Wet strength is the ability to maintain mechanical strength of paper subjected to complete water soaking for extended periods of time, so it is contemplated that a coating of polyamidoamine epichlorohydrin resin on an SiO_(x) barrier coating or layer will have similar resistance to dissolution in aqueous media. It is also contemplated that, because polyamidoamine epichlorohydrin resin imparts a lubricity improvement to paper, it will also provide lubricity in the form of a coating on a thermoplastic surface made of, for example, COC or COP.

Magnetic Treatment During PECVD

The apparatus described and illustrated in this specification, as in FIGS. 4-6, 9-28, and 37 to 46, can be used in any embodiment in this specification to carry out a method of plasma modifying a workpiece 12 having a surface 14 or 16 to be treated. The method can be carried out by providing plasma and, at least part of the time while providing plasma, providing a magnetic field in or near the plasma.

Plasma can be provided in or near the surface 16 of the workpiece 12, specific examples of which are a syringe or cartridge barrel 14 or a vial 10, under conditions effective for plasma modification of the surface 16. Various types of modifications can be contemplated, individually or carried out successively or together, including but not limited to those described previously. For example, the modification can be an etching or ablating process in which the substrate can be eroded, a coating process in which a coating of material can be applied to the substrate, a chemical modification in which the surface 16 can be changed in composition, which optionally can be done without either adding or etching away bulk material. Optionally in any embodiment, the plasma modification of the surface 16 of the workpiece 12 can be chemical vapor deposition. Optionally in any embodiment, the plasma modification of the surface 16 of the workpiece 12 can be plasma enhanced chemical vapor deposition (PECVD).

At least part of the time while providing plasma, a magnetic field can be provided in or near the plasma. The magnetic field can have a position, orientation, and field strength effective to improve the uniformity, density, or both of plasma modification of the surface 16 of the workpiece 12.

Optionally in any embodiment, the surface 16 can be on a generally cylindrical interior wall defining at least a portion of a lumen 18. For example, the surface 16 optionally can be disposed on a vial 10, a syringe barrel or cartridge barrel 14, a sample collection tube, e.g. blood collection tube 268, a rigid or flexible tube, or a flexible sample bag, to provide several examples. The present invention can be also useful for non-cylindrical surfaces. For example, the local magnetic field strength, the material supply, the plasma-forming energy or any combination of these can be varied in different parts of a non-cylindrical container to provide the coating profile, whether uniform or varied, useful in a particular embodiment.

Where a uniform coating profile is desired, as for the barrier coating or layer or the pH protective coating or layer, the desired thickness uniformity range, is +/−30% from the mean thickness, more preferably +/−15% from the mean thickness and most preferably, +/−5% from the mean thickness of the particular coating or layer. A less uniform coating dictates the use of measures, such as magnetic confinement, to increase the coating uniformity.

Optionally in any embodiment, providing the magnetic field improves the uniformity, density, or both of plasma distribution in at least a portion of the lumen. As one non-limiting example, providing the magnetic field can improve the axial uniformity, density, or both of plasma distribution along at least a portion of the surface 16.

Optionally in any embodiment, the plasma can be plasma electrons and the magnetic field can be effective to improve confinement of the plasma electrons in the lumen, as by employing an electronic bottle as described in this specification. The inventors theorize, without intending to be bound by the accuracy or limits of this theory, that this confinement of electrons can be at least partially responsible for more uniformly distributing the plasma and for providing more intense yet uniform ionization of the precursor and other material in the plasma, and thus avoiding hot spots (where many or more energetic electrons collide with the vessel wall) and cool spots (where fewer or less energetic electrons collide) representing areas of differential treatment. Hot spots, for example, can cause areas of the substrate to become distorted or over-treated in the process of providing adequate treatment of the cool spots.

Optionally in any embodiment, the magnetic field can be provided by providing a magnetic field generator (any of 61-78, 86-91, 93, 95, 97, or 99), alternatively at least two magnetic field generators, optionally at least three magnetic field generators, optionally at least four magnetic field generators, optionally at least five magnetic field generators, optionally at least six magnetic field generators, optionally at least seven magnetic field generators, optionally at least eight magnetic field generators, and optionally any desired number of magnetic field generators near the surface 16, each magnetic field generator having a north pole and a south pole defining a polar axis. Optionally in any embodiment, some or all of the magnetic field generators can be placed outside the lumen (18). The principle types of magnetic field generators in common use can be permanent magnets and coils, although the invention is not limited to these types of magnetic field generators. Optionally in any embodiment, at least one magnetic field generator can be a permanent magnet (any of 61-78 or 86-91, 93, 95, 97, or 99) or a coil (for example any of 86-91, 93, 95, 97, or 99) or a combination of at least one permanent magnet and at least one coil. Either coils or permanent magnets can be used analogously to generate similar magnetic fields in various orientations.

Optionally in any embodiment, at least one permanent magnet (any of 61-72), alternatively at least two permanent magnets, alternatively at least three permanent magnets, alternatively at least four permanent magnets, alternatively at least five permanent magnets, alternatively at least six permanent magnets, alternatively at least seven permanent magnets, alternatively at least eight permanent magnets, alternatively all of the permanent magnets are bar magnets. These embodiments are illustrated by FIGS. 15, 16, 18-21, and 24-25. It will be noted that the polar axis of a bar magnet can be, but is not necessarily, parallel to the longest dimension of the bar magnet.

Optionally in any embodiment, at least one permanent magnet (73-78), alternatively at least two permanent magnets, alternatively at least three permanent magnets, alternatively at least four permanent magnets, alternatively at least five permanent magnets, alternatively at least six permanent magnets, alternatively at least seven permanent magnets, alternatively at least eight permanent magnets, alternatively all of the permanent magnets are ring magnets. Ring magnets are shown, for example, in FIGS. 14, 17, 22, 23, 38, 40, 41, 46, and 47, Optionally in any embodiment, as shown in FIGS. 14, 23, 38, 40, 41, 46, and 47, the north and south poles of at least one of the ring magnets (75-78) are its opposed annular faces.

Optionally in any embodiment, the polar axis (79) of at least one of the ring magnets (e.g. 73 or 74) can be circumferential about the ring as shown in FIGS. 17 and 22, as is also the case with the toroidal coils discussed below. Optionally in any embodiment, the circumference of at least one of the ring magnets (73 or 74) can be divided into plural north-south pole domains.

Optionally in any embodiment, at least part of the time while providing the magnetic field, the magnetic field generator can be provided by positioning at least one coil (any of 86-91, 93, 95, 97, or 99) near the surface and conducting an electrical current through the coil.

Optionally in any embodiment, at least one coil can be a solenoid 86. The solenoid optionally can be oriented with its axis 79 at least generally parallel to the axis 80 of the surface, alternatively with its axis 79 at least generally collinear with the axis 80 of the surface. Optionally in any embodiment, the surface can be located entirely within the solenoid coil (86).

Optionally in any embodiment, at least one coil can be, or include, a generally toroidal coil 88 or 90 having a central opening and a geometric axis 79 passing through its central opening, as illustrated in FIGS. 10-13. Optionally in any embodiment, at least part of the time while providing the magnetic field, the generally toroidal coil 88 or 90 can be oriented with its geometric axis 79 at least generally parallel, optionally at least generally collinear with the axis 80 of the surface 16. In this orientation of a toroidal coil the magnetic field in at least a portion of the lumen 18 is oriented with its polar axis extending around the axis 80 of the surface 16 to be treated. Optionally in any embodiment, at least part of the time while providing the magnetic field, the surface 16 can be located substantially entirely within the central opening, alternatively substantially entirely within the central openings of a stack of two or more of the generally toroidal coils 88 or 90.

Optionally in any embodiment, illustrated in FIG. 12 for example, the generally toroidal coils 88 or 90 can have at least two arc segments A and A1, optionally at least four arc segments A and A1, optionally at least 6 arc segments A and A1, optionally at least eight arc segments A and A1, optionally at least eight 45° arc segments A and A1. Optionally in any embodiment, alternating segments can be wound in opposite directions.

Optionally in any embodiment, the generally toroidal coils 88 or 90 can have cross-sections that can be substantially circular 95 or substantially rectangular 91 or another regular or irregular shape.

A coil can have a full length core, a partial length core, a solid core, a hollow core, or no core, and the core can be a permanent magnet that generates a magnetic field in itself, a temporarily magnetizable material that generates a magnetic field when energized by the coil, or a magnetically inactive form for winding the coil. A conventional magnetizable core material is an iron or ferrite body.

Optionally in any embodiment, the coil can be energized with DC or AC energy. It is contemplated that a coil energized with AC energy, for example 60 Hz alternating current, will periodically reverse poles, which is contemplated to improve the uniformity of deposition or other surface treatment, much like the moving quadrupole array described below functions.

Optionally in any embodiment, two or more magnetic field generators can be spaced to define a recess 81 between them, within which at least a portion of the surface 16 of the workpiece can be positioned.

Various orientations of the magnetic fields have been found to be useful in improving the uniformity or other results of PECVD treatment. As one example, at least part of the time while providing the magnetic field, a magnetic field generator (any of 61-78 or 86-91, 93, 95, 97, or 99), alternatively at least two of the magnetic field generators, alternatively at least three of the magnetic field generators, alternatively at least four of the magnetic field generators, alternatively at least five of the magnetic field generators, alternatively at least six of the magnetic field generators, alternatively at least seven of the magnetic field generators, alternatively at least eight of the magnetic field generators, alternatively all of the magnetic field generators, can have their polar axes 78 generally parallel to the axis 80 of the surface 16. Examples of this orientation are found in FIGS. 9, 9 a, 14-16, 20, 23, 24, 37, magnets 75 of FIGS. 38 and 40, and FIGS. 41-44 and 46, for example, optionally can have polar axes (78) generally parallel to the axis (80) of the surface (16). Where the surface (16) is generally cylindrical, its axis is the center of the cylinder. For a non-cylindrical surface the axis can be any particular line passing through the surface.

As another example, at least part of the time while providing the magnetic field, at least two of the magnetic field generators (any of 61-78 or 86-91, 93, 95, 97, or 99), alternatively at least three of the magnetic field generators, alternatively at least four of the magnetic field generators, alternatively at least five of the magnetic field generators, alternatively at least six of the magnetic field generators, alternatively at least seven of the magnetic field generators, alternatively at least eight of the magnetic field generators, alternatively all of the magnetic field generators, can be circumferentially distributed around the surface 16 when the workpiece and magnetic field generators are in the operative position for plasma treatment, as illustrated in FIGS. 4, 5, 9-9 a, 10-14, 19-25, and 37-46, for example. The circumferential distribution can be even or uneven, although even distribution is specifically contemplated as one alternative.

Optionally in any embodiment, an even number of at least four magnetic field generators (for example, the magnets 61-64 or 61 a-64 a of FIGS. 19, 21, 25, 38-40, 45, and 48) are arranged about a center, with their polar axes alternately oriented radially toward the center and away from the center to provide a quadrupole or analogous structure. Quadrupoles are discussed further below in connection with electron bottles.

Optionally in any embodiment, at least part of the time while providing the magnetic field, at least two of the magnetic field generators, alternatively at least three of the magnetic field generators, alternatively at least four of the magnetic field generators, alternatively at least five of the magnetic field generators, alternatively at least six of the magnetic field generators, alternatively at least seven of the magnetic field generators, alternatively at least eight of the magnetic field generators, alternatively all of the magnetic field generators, can be substantially circumferentially equidistant from the adjacent magnetic field generators when the workpiece and magnetic field generators are in the operative position. This is illustrated in FIGS. 4, 5, 19-21, 24-25, and 38-40, and 45, for example.

Optionally in any embodiment, at least part of the time while providing the magnetic field, at least two of the magnetic field generators (any of 61-78 or 86-91, 93, 95, 97, or 99), alternatively at least three of the magnetic field generators, alternatively at least four of the magnetic field generators, alternatively at least five of the magnetic field generators, alternatively at least six of the magnetic field generators, alternatively at least seven of the magnetic field generators, alternatively at least eight of the magnetic field generators, alternatively all of the magnetic field generators, can be axially stacked with respect to the generally cylindrical surface, as illustrated for example in FIGS. 10-13, 22-24, 37-41, and 46, and usable to form any illustrated magnetic field generator. Additionally, the axially oriented solenoid coils of FIGS. 9, 9 a, 37 referring to either coil 86 a or 86 b), and 42-43 are conceptually similar, as the successive turns are “stacked” axially as well, and each is a magnetic field generator from a more granular perspective.

Optionally in any embodiment, at least part of the time while providing the magnetic field, at least two of the axially stacked magnetic field generators (any of 61-78 or 86-91, 93, 95, 97, or 99), alternatively at least three of the axially stacked magnetic field generators, alternatively at least four of the axially stacked magnetic field generators, alternatively at least five of the axially stacked magnetic field generators, alternatively at least six of the axially stacked magnetic field generators, alternatively at least seven of the axially stacked magnetic field generators, alternatively at least eight of the axially stacked magnetic field generators, alternatively all of the axially stacked magnetic field generators, can be axially spaced from each other. This orientation is illustrated, for example, in FIGS. 23, 37, 38, and 47.

Optionally in any embodiment, at least part of the time while providing the magnetic field, at least two of the axially stacked magnetic field generators (any of 61-78 or 86-91, 93, 95, 97, or 99), alternatively at least three of the axially stacked magnetic field generators, alternatively at least four of the axially stacked magnetic field generators, alternatively at least five of the axially stacked magnetic field generators, alternatively at least six of the axially stacked magnetic field generators, alternatively at least seven of the axially stacked magnetic field generators, alternatively at least eight of the axially stacked magnetic field generators, alternatively all of the axially stacked magnetic field generators, axially abut each other.

Optionally in any embodiment, at least part of the time while providing the magnetic field, at least one magnetic field generator can be oriented with its polar axis 79 at least generally parallel to the axis 80 of the surface. Alternatively or in addition, at least part of the time while providing the magnetic field, at least one magnetic field generator can be oriented with its polar axis 79 at least generally collinear with the axis 80 of the surface. These orientations are illustrated by FIGS. 9, 9 a, 20, 24, 37, 38 and 40 (magnets 75), 41-44, 46, and 47, for example.

Optionally in any embodiment, at least part of the time while providing the magnetic field, the magnetic field generator can have a passage extending along its polar axis and the surface can be located entirely within the passage. These orientations are illustrated by FIGS. 9, 9 a, 20, 24, 37, 38 and 40 (magnets 75), 41-44, 46, and 47, for example.

Optionally in any embodiment, the magnetic field generator can be a Helmholtz coil, which, as illustrated in FIG. 37, can be a pair of solenoids 86 a and 86 b with space between them. In a Helmholtz coil, the space between the solenoids 86 a and 86 b, if not too great, provides a substantially uniform magnetic field in the space between the solenoids. Optionally in any embodiment, the space between the first and second spaced solenoids 86 a and 86 b optionally provides a viewing window allowing the plasma to be viewed while the method is in progress (to the extent it can be seen through other apparatus). For example, the electrode 160 (FIG. 4) optionally can be U-shaped (in an alternative from FIGS. 5 and 9) and the vessel wall 14 can be transparent, thus allowing the plasma to be viewed easily.

Optionally in any embodiment, at least part of the time while providing the magnetic field, the magnetic field generator can provide a field strength that varies along the workpiece surface 16. This varying field strength can be provided in various ways. Optionally in any embodiment, at least part of the time while providing the magnetic field, the distance between at least one magnetic field generator and the workpiece surface can vary along the workpiece surface 16, as illustrated in FIG. 47. As another example, at least part of the time while providing the magnetic field, the field strength can vary along the workpiece surface to define a profile of varying field strength, shown for example in FIGS. 9a , 23, 37 (the Helmholtz coils minimize the non-uniformity, but some may persist in certain embodiments), 38, 41-44, 46, and 47-48.

Optionally in any embodiment, at least part of the time while providing the plasma and not providing the magnetic field, the plasma modification of the surface 16 of the workpiece 12 varies along the workpiece surface to define a profile of varying plasma modification. In other words, without applying the magnetic field, the degree or kind of plasma modification at various points on the workpiece surface might not be uniform for given apparatus operated under given conditions. This variation might be desirable or undesirable. If undesirable in a particular embodiment, at least part of the time while providing the magnetic field, the magnetic field generators can be configured and operated under conditions such that variations in the profile of magnetic field strength tend to counteract variations of plasma modification. By counteracting variations in the plasma process with magnetic variations, the uniformity, density, or both of plasma modification of the surface 16 of the workpiece 12 can be made more uniform.

Optionally in any embodiment, at least part of the time while providing the magnetic field, at least a portion of the plasma can be at least partially confined to the vicinity of the workpiece in an “electron bottle.” Electron bottles can be created in various ways.

One example of an electron bottle is shown in FIGS. 38-40. The side of the electron bottle can be a quadrupole formed by the magnets 61, 62, 63, and 64 arranged with their north poles alternatively extending radially toward and radially away from the workpiece 10. As FIG. 39 shows, this quadrupole orientation produces magnetic lines 83 arcing from radially inward at one magnet to radially outward at the adjacent magnet, providing a pattern resembling four-sided closed loops in any radial plane. Electrons travel helically around and along the magnetic lines 83, thus in a circuit around and within the workpiece 10. This confines the electrons radially to the space 81 enclosed by the magnets.

The ends of the electron bottle can be defined in FIGS. 38 and 40 by ring magnets 75 that have a smaller diameter, and a greater field strength, than the magnets 61-64 around the perimeter. The ring magnets 75 can be oriented with their polar axes aligned with the geometric axes of the quadrupole 61-64 and workpiece 10. FIG. 38 shows that the magnetic field lines bow out and can be further apart at an axial distance away from the ring magnets 75 (since these generally axial lines can be primarily generated by the ring magnets 75), indicating a lower magnetic flux near the axial center of the quadrupole than within the magnets 75. The ring magnets 75 thus act as opposed electron mirrors, tending to reverse the direction of travel of electrons approaching them back toward the workpiece 10.

FIG. 41 shows a different type of electron bottle, and in this case the workpiece can be a syringe body and needle assembly 12, the assembly having a needle end, a back end opposite the needle end, and a body portion between the needle end and back end. The electron bottle of FIG. 41 can be defined by a stack of ring magnets 75, all oriented with their north poles toward the top of the sheet and their south poles toward the bottom of the sheet. The ends of the electron bottle can be bar magnets 65, sometimes referred to as cap magnets, that have no central aperture and have the same magnetic orientation as the ring magnets 65, with their north poles toward the top of the sheet. Since the cap magnets 65 can be made of magnetically permeable material, the flux can be stronger within the body of each cap magnet than outside it on either side, so the cap magnets act as electron mirrors. The magnetic lines of FIG. 41, if shown, would look much like the magnetic lines 83 of FIG. 42.

FIGS. 9a and 42 show electron bottles formed by a coil having a central portion 89 providing a generally axially extending magnetic field adjacent to a central portion of the vial 10 and end portions 97 and 99 providing a similarly oriented magnetic field having a stronger flux than the central portion 89. The end portions 97 and 99 provide a stronger flux because the windings of the end portions can be closer together than those of the central portion 89. The end portions 97 and 99 also provide a stronger flux because the voltage drop across the central portion can be 30 Volts (as an illustration, not limiting the scope of the invention), while the voltage drop across each of the end portions can be 60 Volts (as an illustration, not limiting the scope of the invention), and the resistance of each end portion 97, 99 can be the same as the resistance of the central portion 89 (as an illustration, not limiting the scope of the invention), so the amperage flowing through the end portions 97, 99 can be higher than that flowing through the central portion 89. This difference in flux is reflected by the magnetic lines 83, as indicated before. Thus, the end portions 97 and 99 again define opposed electron mirrors. Either expedient for increasing the flux at the ends of the electron bottle can be used independently, as other alternatives.

FIG. 43 shows another type of electron bottle formed by a solenoid having a uniform winding 89, forming a magnetic field represented by generally parallel magnetic lines 83. The magnetic field constrains electrons to travel along a corkscrew or helical axial path 103. A charged capacitor 101 can be placed at each end of the solenoid, with the respective negatively charged plates facing toward the solenoid and the positively charged plates facing away from the solenoid. The negatively charged plates act as electron mirrors, repel approaching electrons, returning them to the interior of the solenoid. FIG. 43 differs from the electron bottles of FIGS. 9a and 38-42 in that the mirrors reflecting electrons back into the bottle can be electrostatic rather than magnetic. For the present purposes, it is still considered a “electron bottle,” as it functions in an analogous manner to confine electrons.

FIG. 44 shows another type of electron bottle in which ring magnets 75 (alternatively other types of magnetic field generators such as solenoids) at each end define electron mirrors and the electrons can be also laterally confined by an inner, negatively charged shell electrode 107 disposed within an outer, positively charged shell electrode 109. Again, the electrons can be reflected or repelled inward toward the axis of the apparatus. This apparatus also can have the advantage that positively charged ions formed within the vial 10 can be attracted toward the wall of the vial as it is treated by the plasma, while electrons can be repelled inward, which tends to keep the walls cooler during operation. The walls of the vial 10 confine the ions so they cannot escape.

An alternative to FIG. 44 would be to use the external electrode 160 as the negatively charged shell 107 and the inner electrode 108 as the positively charged counter electrode. This can be done by adding a DC bias voltage to the electrodes 108 and 160, as well as the RF alternating current. This construction would have the similar result of attracting electrons in the vial 10 away from its walls and the positively charged ions in the vial 10 toward its walls.

Moreover, the individual features of any of the embodiments of FIGS. 1-29 and 36 to 44 can be substituted in any of those embodiments, without limitation. For example, any of the axial electron mirrors defined by the ring magnets 75 of FIG. 38 or 44, the cap magnets 65 of FIG. 41, the solenoid windings 97 and 99 of FIGS. 9a and 42, and the electrostatic plates 101 of FIG. 43 can be used individually in any of the embodiments of FIGS. 1-29 and 36 to 44, and can be used in any combination in any of those embodiments. The same can be true of the expedients for radial confinement, such as the quadrupole magnets 61-64 of FIG. 38, the ring magnets 75 of FIG. 41, the solenoid winding 89 of FIG. 42 or 43, the electrostatic shells 107 and 109, or a bias between the inner and outer electrodes 108 and 160. Any of these electronic bottle features can be used in any embodiment, individually or in any combination, and can be used with any type of workpiece such as vials 10, capped pre-assemblies 12, syringe or cartridge barrels 14, sample tubes 210, or others of FIGS. 1-3, 7-8, 29, and 36, and with any plasma generation and material feed and exhaust apparatus or combination or substitution of apparatus, such as that of FIG. 4-6, 9-28, or 37-44.

Thus, optionally in any syringe embodiment of the invention, for example one in which the workpiece is a syringe or cartridge barrel 14 or syringe body and needle assembly 12, any of which have a needle end (whether or not the needle is present at the time), a back end opposite the needle end, and a body portion between the needle end and back end, the electron bottle can be defined by structure providing a stronger magnetic field at or near the needle end than at or near at least part of the body portion.

Optionally in any syringe embodiment of the invention, the electron bottle can be defined by structure providing a stronger magnetic field at or near the back end than at or near at least part of the body portion, illustrated in FIG. 9 and 9 a, 37-42, or 44, for example. The electron bottle can be defined by structure providing stronger magnetic fields at or near the needle end and the back end than at or near at least part of the body portion, illustrated in the same Figures. The electron bottle can be defined by structure providing an electron mirror at or near the needle end, as shown in FIGS. 9, 9 a, 23, 37, 41, and in FIGS. 38-40, 42-44, and 47 if a syringe is substituted for the illustrated vial 10. The electron bottle can be further defined by structure providing an electron mirror at or near the back end, as in the same FIGS. 9, 9 a, 23, 37, 41, and in FIGS. 38-40, 42-44, and 47 if a syringe is substituted for the illustrated vial 10.

For embodiments in which the workpiece is a vial 10 having an open end, a closed end, and a body portion between the ends, the electron bottle can be defined by structure providing a stronger magnetic field at or near the closed end of the vial than at or near at least part of the body portion of the vial as in the Figures mentioned in connection with syringe treatment or vial treatment above. The electron bottle can be defined by structure providing a stronger magnetic field at or near the open end of the vial than at or near at least part of the body portion of the vial. The electron bottle can be defined by structure providing stronger magnetic fields at or near the closed end and the open end of the vial than at or near at least part of the body portion of the vial. The electron bottle can be defined by structure providing an electron mirror at or near the closed end of the vial. The electron bottle can be further defined by structure providing an electron mirror at or near the open end of the vial.

Optionally in any embodiment, the structure providing an electron mirror can be at least a portion of a magnetic field generator, as in FIGS. 9, 9 a, 23, 37-42, 44, and 47-48 (in FIG. 48, the lower portions of the magnets 61 and 62 provide a stronger magnetic field than the upper portions of the same magnets, thus a magnetic mirror). Optionally in any embodiment, the structure providing an electron mirror can comprise a ferromagnetic material, as in any of the permanent magnet embodiments of FIGS. 23, 38-41, and 47-48. Optionally in any embodiment, the structure providing an electron mirror can comprise a ferrimagnetic material, such as the cores on which the windings of coils are supported in FIG. 9-13, 37, 42, or 43. Optionally in any embodiment, the structure providing an electron mirror can be a negatively charged object or portion of an object, shown for example in FIGS. 43 (axial mirrors) and 44 (radial mirror

In the embodiment of FIG. 49, the magnets 65-72 are axial, meaning that their polar axes extend along their length, and they are arrayed to provide a strong axially extending magnetic field through the apertures that receive the syringe or other vessel being processed. They do not define a quadrupole. The magnets 65-72 can be, for example, NdFeB magnets providing a very strong magnetic field. The inventors contemplate that these magnets can improve the uniformity of deposition of PECVD coatings without rotating the magnet array, although they can be rotated to, for example, compensate for any deviations from concentricity or equal magnetic strength of the assembly in use.

Optionally in any embodiment, at least one magnetic field generator 73-78, alternatively at least two magnetic field generators, alternatively at least three magnetic field generators, alternatively at least four magnetic field generators, alternatively at least five magnetic field generators, alternatively at least six magnetic field generators, alternatively at least seven magnetic field generators, alternatively at least eight magnetic field generators, alternatively all of the magnetic field generators can be ring magnets having central apertures sized to receive the workpiece surface 16, as shown in any of FIG. 14, 22, 23, 38, 40, 41, 46, or 47.

Optionally in any embodiment, the north and south poles of at least one of the ring magnets 75-78 can be its opposed annular faces as shown in any of FIG. 14, 22, 23, 38, 40, 41, 46, or 47. Optionally in any embodiment, the magnetic field can be provided at least in part by a stack of:

-   -   at least one interior ring magnet having the workpiece surface         16 within its central recess when in its operative position, and     -   at least one cap magnet axially aligned with but outside the         stack of interior ring magnets, the cap magnet comprising either         a ring magnet or a bar magnet, in which the interior ring         magnets provide a first magnetic field strength radially         adjacent to the workpiece surface 16 that is less than the         magnetic field strength provided by the cap magnet axially         adjacent to the workpiece surface 16. This construction is         illustrated, for example, in FIG. 41, and other Figs. show         multiple ring magnets that can be adapted to provide the same         construction.

Optionally in any embodiment, one or more additional magnets can be positioned between a cap magnet and the stack of interior ring magnets illustrated, for example, in FIG. 41. Optionally in any embodiment, the polar axis 79 of at least one of the ring magnets 73 or 74 can be circumferential about the ring as shown in FIGS. 17 and 22. Optionally in any embodiment, the circumference of at least one of the ring magnets 73 or 74 can include plural north-south pole domains as shown in FIGS. 17 and 22.

Optionally in any embodiment, at least part of the time while providing the magnetic field, an even number of at least four magnetic field generators 61-64 or 61 a-64 a can be arranged about an axis to provide a quadrupole or analogous structure, as shown in FIG. 4-6, 21, 25, 38-40, 45, or 48. Optionally in any embodiment, the magnetic field generators can be relatively movable between an effective position providing the quadrupole or analogous structure and a non-functional position in which the magnetic field generators do not provide a quadrupole or analogous structure. Optionally in any embodiment, at least part of the time while providing the magnetic field, the quadrupole and workpiece can be relatively positioned with the axis passing through the workpiece surface.

Optionally in any embodiment, at least part of the time while providing the magnetic field, the quadrupole can be effective to at least partially confine the plasma at or near at least a portion of the workpiece surface. Optionally in any embodiment, at least part of the time while providing the magnetic field, a magnetic field generator having an axial polar axis can be positioned at or near at least one of the axially spaced ends. Optionally in any embodiment, at least part of the time while providing the magnetic field, magnetic field generators having axial polar axes can be positioned at or near both of the axially spaced ends.

Optionally in any embodiment, at least one of the magnetic field generators having axial polar axes can be a ring magnet. Optionally in any embodiment, at least one of the magnetic field generators having axial polar axes can be a cap magnet. Optionally in any embodiment, at least one of the magnetic field generators having axial polar axes can be a bar magnet.

Optionally in any embodiment, at least part of the time while providing the magnetic field, a magnetic field generator (any of 61-78 or 86-91, 93, 95, 97, or 99), alternatively at least two of the magnetic field generators, alternatively at least three of the magnetic field generators, alternatively at least four of the magnetic field generators, alternatively at least five of the magnetic field generators, alternatively at least six of the magnetic field generators, alternatively at least seven of the magnetic field generators, alternatively at least eight of the magnetic field generators, alternatively all of the magnetic field generators, can be rotated about the surface 16, or the surface can rotate with respect to one, more than one, or all of the magnetic field generators, or both, during at least a portion of the plasma treatment. This is illustrated in or usable with the embodiments of FIGS. 4-6, 19-28, and 37-46, for example.

Referring in particular to FIG. 19, the illustrated quadrupole array can be rotated, for example at 10-1000 rpm, alternatively 40 to 200 RPM, to improve the uniformity of the deposition of PECVD coatings within the perimeter of the magnets. For example, a rotation rate of 47 RPM has been used successfully, aothough faster rotation than that is contemplated to improve uniformity.

Optionally in any embodiment, at least one magnetic field generator, the workpiece surface, or both, can be rotated at a rate effective to improve the uniformity, density, or both of the average magnetic field strength, or to improve the uniformity, reduce the intensity, or both of workpiece heating about a circumference of the workpiece surface, as illustrated in the working examples. Optionally in any embodiment, the rotation can be concentric or eccentric. Concentric rotation or closely circumferentially spaced magnetic field generators or uniform magnetic field strength generated by the various generators, or any combination of two or more of these, can be contemplated to provide more uniform treatment of the whole surface at the same time, while eccentric rotation or more widely circumferentially spaced magnetic field generators or variations in the magnetic strength of the magnetic field generators, or any combination of two or more of these, can be contemplated to periodically increase and decrease the magnetic field strength and heating at any particular point around the circumference of the treated surface, allowing a particular point around the circumference some cooling time between more intense applications of magnetic energy.

Instead or in addition to rotation of the magnetic field generators, the workpiece surface can rotate with respect to one, more than one, or all of the magnetic field generators, or both, during at least a portion of the plasma treatment. This is illustrated in or usable with the embodiments of FIGS. 4-6, 19-28, and 37-46, for example.

Optionally in any embodiment, at least part of the time while providing the magnetic field, at least one of the magnetic field generators can be translated (moved in a straight line), for example axially, along the workpiece surface, or the workpiece surface can be translated with respect to the magnetic field generator, or both, at a rate effective to improve the uniformity of workpiece heating along the axis of the workpiece surface. The embodiments of FIGS. 4-6, 9, 9 a-13, 19-28, and 37-46, for example, can be operated while translating the magnetic field generator, and thus the magnetic field.

Optionally in any embodiment, an array of coils employed as magnetic field generators can be energized in a way causing the magnetic field about the workpiece to move, without physical motion of the coils or workpiece. For example, a series of eight solenoids arranged to form a quadrupole about a center, with their axes oriented radially, can be energized with alternating current with the phase of each coil 45 degrees ahead of the coil to its left and 45 degrees behind the coil to its right. As the phases change, the effect is similar to that provided by rotating the same quadrupole about its center, with its adjacent magnets energized with constant DC currents of opposite direction.

Optionally in any embodiment the PECVD parameters are controlled such that the distance between the inlet tube and the wall of the syringe barrel or other part undergoing PECVD is:

-   -   greater than the Debye Length,     -   optionally at least 2 times as great as the Debye Length,     -   optionally at least 3 times as great as the Debye Length,     -   optionally at least 4 times as great as the Debye Length,     -   optionally at least 5 times as great as the Debye Length,     -   optionally at least 6 times as great as the Debye Length,     -   optionally at least 7 times as great as the Debye Length,     -   optionally at least 8 times as great as the Debye Length,     -   optionally at least 9 times as great as the Debye Length,     -   optionally at least 10 times as great as the Debye Length,     -   optionally at least 20 times as great as the Debye Length,     -   optionally at least 30 times as great as the Debye Length,     -   optionally at least 40 times as great as the Debye Length,     -   optionally at least 50 times as great as the Debye Length,     -   optionally at least 60 times as great as the Debye Length,     -   optionally at least 70 times as great as the Debye Length,     -   optionally at least 80 times as great as the Debye Length,     -   optionally at least 90 times as great as the Debye Length,     -   optionally at least 100 times as great as the Debye Length.

The Debye Length is defined by the following equation:

$\lambda_{D} = \left. \sqrt{}\frac{ɛ_{0}{k_{B}/q_{e}^{2}}}{{n_{e}/T_{e}} + {\sum\limits_{ij}\; {j^{2}{n_{ij}/T_{i}}}}} \right.$

in which AD is the Debye length,

ε₀ is the permittivity of free space,

k_(B) is the Boltzmann constant,

q_(e) is the charge of an electron,

T_(e) and T_(i) are the temperatures of the electrons and ions, respectively,

n_(e) is the density of electrons,

nij is the density of atomic species i, with positive ionic charge jq_(e)

Optionally in any embodiment, the uniformity of plasma modification can be expressed as a ratio of:

one standard deviation of coating thickness:mean coating thickness and the ratio can be less than 0.69, alternatively from 0.69 to 0.01, alternatively from 0.69 to 0.05, alternatively from 0.66 to 0.1, alternatively from 0.66 to 0.2, alternatively from 0.66 to 0.21, alternatively less than 0.6, alternatively from 0.6 to 0.01, alternatively from 0.6 to 0.05, alternatively from 0.6 to 0.1, alternatively from 0.6 to 0.2, alternatively from 0.6 to 0.21, alternatively less than 0.5, alternatively from 0.5 to 0.01, alternatively from 0.5 to 0.05, alternatively from 0.5 to 0.1, alternatively from 0.5 to 0.2, alternatively from 0.5 to 0.21, alternatively less than 0.4, alternatively from 0.4 to 0.01, alternatively from 0.4 to 0.05, alternatively from 0.4 to 0.1, alternatively from 0.4 to 0.2, alternatively from 0.4 to 0.21, alternatively less than 0.3, alternatively from 0.3 to 0.01, alternatively from 0.3 to 0.05, alternatively from 0.3 to 0.1, alternatively from 0.3 to 0.2, alternatively from 0.3 to 0.21.

Optionally in any embodiment, the plasma modification can be application of a coating having a mean thickness between 1 and 1000 nm and a standard deviation of less than 190 nm, alternatively from 190 to 10 nm, alternatively from 190 to 20 nm, alternatively from 190 to 30 nm, alternatively from 190 to 40 nm, alternatively from 190 to 50 nm, alternatively from 190 to 60 nm, alternatively from 190 to 70 nm, alternatively from 190 to 80 nm, alternatively less than 161 nm, alternatively from 160 to 10 nm, alternatively from 160 to 20 nm, alternatively from 160 to 30 nm, alternatively from 160 to 40 nm, alternatively from 160 to 50 nm, alternatively from 160 to 60 nm, alternatively from 160 to 70 nm, alternatively from 160 to 80 nm, alternatively less than 140 nm, alternatively from 140 to 10 nm, alternatively from 140 to 20 nm, alternatively from 140 to 30 nm, alternatively from 140 to 40 nm, alternatively from 140 to 50 nm, alternatively from 140 to 60 nm, alternatively from 140 to 70 nm, alternatively from 140 to 80 nm, alternatively less than 122 nm, alternatively from 120 to 10 nm, alternatively from 120 to 20 nm, alternatively from 120 to 30 nm, alternatively from 120 to 40 nm, alternatively from 120 to 50 nm, alternatively from 120 to 60 nm, alternatively from 120 to 70 nm, alternatively from 120 to 80 nm, alternatively less than 100 nm, alternatively from 100 to 10 nm, alternatively from 100 to 20 nm, alternatively from 100 to 30 nm, alternatively from 100 to 40 nm, alternatively from 100 to 50 nm, alternatively from 100 to 60 nm, alternatively from 100 to 70 nm, alternatively from 100 to 80 nm, alternatively less than 80 nm, alternatively from 80 to 10 nm, alternatively from 80 to 20 nm, alternatively from 80 to 30 nm, alternatively from 80 to 40 nm, alternatively from 80 to 50 nm, alternatively from 80 to 60 nm, alternatively from 80 to 70 nm.

Magnetic Treatment Apparatus

Additional details of apparatus usable in any embodiment for plasma modifying a workpiece 12 supported on a workpiece support 114 in the presence of a magnetic field are illustrated for example in FIGS. 4, 5, 6, and 9, and in some cases others. The apparatus includes the workpiece support 114 for holding a workpiece 12 in the apparatus, a plasma generator, and a magnetic field generator. The plasma generator here includes an inner electrode such as 108 (optionally further including any of the features 120 to 142, for example), an outer electrode such as 160, power supply 162, material supplies through the gas delivery port 110. The magnetic field generator in FIGS. 4-5 optionally can be any of the magnets 61,62,63, and 64 (alternatively in the respective embodiments including any of the magnets 61-78, coils 86-99, or electrodes 107 or 109, for example).

The workpiece 12 used in any embodiment optionally has a lumen 18 surrounded by a wall 16. At least part of the wall 16, here, substantially the entire interior surface, can define a surface to be treated.

The plasma generator can be used for providing plasma within the lumen 18 of a workpiece 12 supported on the workpiece support 114 under conditions effective for plasma modification of the surface 16 of the workpiece 12.

The magnetic field generator can be used for providing a magnetic field in at least a portion of the lumen 18 of a workpiece 12 supported on the workpiece support 114. The resulting magnetic field can have an orientation and field strength effective to improve the uniformity, density, or both of plasma modification of the interior surface of the generally cylindrical wall 16.

Optionally in any embodiment, at least one magnetic field generator, alternatively at least two magnetic field generators, optionally at least three magnetic field generators, optionally at least four magnetic field generators, optionally at least five magnetic field generators, optionally at least six magnetic field generators, optionally at least seven magnetic field generators, optionally at least eight magnetic field generators can be located outside a workpiece 12 in their operative position.

Optionally in any embodiment, the interior portion 81 of the solenoid 86 can be an interior winding 89. At least one of the end portions 86 or 87 providing a stronger magnetic field when energized can be a separate exterior winding 97 or 99. For example, the interior winding 89 can be provided with lower amperage than the separate exterior winding 97 or 99 when the windings can be energized, or the interior winding 89 can have fewer total turns per cm of the axis than the exterior winding 97 or 99.

As a more specific, non-limiting example, the solenoid can have a single winding extending along the interior portion 81 and the first and second opposed end portions 86 and 87, the winding having more turns per cm along the axis at or near the first and second opposed end portions 86 and 87 than along the interior portion 81.

Optionally in any embodiment, magnetic field generators can be arranged to provide the following capabilities, individually or in combination: The material supply tube 104 can rotate with respect to the magnetic field provided by the magnetic field generators (any of 61-78 or 86-91, 93, 95, 97, or 99) and the workpiece support 114. The magnetic field provided by the magnetic field generators can rotate with respect to the material supply tube and the workpiece support. The workpiece support can rotate with respect to the material supply tube and the magnetic field provided by the magnetic field generators. The material supply tube and the magnetic field provided by the magnetic field generators can rotate at the same or different rotation rates and directions with respect to the workpiece support. The magnetic field provided by the magnetic field generators and the workpiece support can rotate at the same or different rotation rates and directions with respect to the material supply tube. The material supply tube and the workpiece support can rotate at the same or different rotation rates and directions with respect to the magnetic field provided by the magnetic field generators.

Optionally in any embodiment, apparatus can be provided for measuring plasma characteristics. As one example, an optical detector 350, for example a camera, can be provided and configured to show whether the plasma in a container includes streamers of non-uniform plasma versus a complete fill of the exposed portions of the container with uniform plasma. As another example, an optical emissions spectrometer can be provided to determine the uniformity of the plasma spectrum. As still another example, a Rogowski Coil 352 disposed about the inner electrode or its power supply conductor to determine the uniformity of the current supplied to the plasma. As even another example, a Langmuir probe 354 can be provided to measure the electron temperature of the plasma. The probe 354 can either be mounted on the internal electrode 108 or provided as a separate part or system.

Fluid Material

Optionally for any of the embodiments of FIGS. 7-8, 29, and 36, the fluid material 40 contained in a pharmaceutical or other fluid package can have a pH between 5 and 6, optionally between 6 and 7, optionally between 7 and 8, optionally between 8 and 9, optionally between 6.5 and 7.5, optionally between 7.5 and 8.5, optionally between 8.5 and 9.

Optionally for any of the embodiments of FIGS. 7-8 and 29, the fluid material 40 can be a liquid at 20° C. and ambient pressure at sea level, which is defined as a pressure of 760 mm Hg.

Optionally for any of the embodiments of FIGS. 7-8 and 29, the fluid material 40 can be an aqueous liquid.

Optionally for any of the embodiments of FIGS. 7-8 and 29, the fluid material 40 comprises a member or a combination of two or more members selected from the group consisting of:

Inhalation Anesthetics

-   -   Aliflurane     -   Chloroform     -   Cyclopropane     -   Desflurane (Suprane)     -   Diethyl Ether     -   Enflurane (Ethrane)     -   Ethyl Chloride     -   Ethylene     -   Halothane (Fluothane)     -   Isoflurane (Forane, Isoflo)     -   Isopropenyl vinyl ether     -   Methoxyflurane     -   methoxyflurane,     -   Methoxypropane     -   Nitrous Oxide     -   Roflurane     -   Sevoflurane (Sevorane, Ultane, Sevoflo)     -   Teflurane     -   Trichloroethylene     -   Vinyl Ether     -   Xenon

Injectable Drugs

-   -   Ablavar (Gadofosveset Trisodium Injection)     -   Abarelix Depot     -   Abobotulinumtoxin A Injection (Dysport)     -   ABT-263     -   ABT-869     -   ABX-EFG     -   Accretropin (Somatropin Injection)     -   Acetadote (Acetylcysteine Injection)     -   Acetazolamide Injection (Acetazolamide Injection)     -   Acetylcysteine Injection (Acetadote)     -   Actemra (Tocilizumab Injection)     -   Acthrel (Corticorelin Ovine Triflutate for Injection)     -   Actummune     -   Activase     -   Acyclovir for Injection (Zovirax Injection)     -   Adacel     -   Adalimumab     -   Adenoscan (Adenosine Injection)     -   Adenosine Injection (Adenoscan)     -   Adrenaclick     -   AdreView (Iobenguane I 123 Injection for Intravenous Use)     -   Afluria     -   Ak-Fluor (Fluorescein Injection)     -   Aldurazyme (Laronidase)     -   Alglucerase Injection (Ceredase)     -   Alkeran Injection (Melphalan Hcl Injection)     -   Allopurinol Sodium for Injection (Aloprim)     -   Aloprim (Allopurinol Sodium for Injection)     -   Alprostadil     -   Alsuma (Sumatriptan Injection)     -   ALTU-238     -   Amino Acid Injections     -   Aminosyn     -   Apidra     -   Apremilast     -   Alprostadil Dual Chamber System for Injection (Caverject         Impulse)     -   AMG 009     -   AMG 076     -   AMG 102     -   AMG 108     -   AMG 114     -   AMG 162     -   AMG 220     -   AMG 221     -   AMG 222     -   AMG 223     -   AMG 317     -   AMG 379     -   AMG 386     -   AMG 403     -   AMG 477     -   AMG 479     -   AMG 517     -   AMG 531     -   AMG 557     -   AMG 623     -   AMG 655     -   AMG 706     -   AMG 714     -   AMG 745     -   AMG 785     -   AMG 811     -   AMG 827     -   AMG 837     -   AMG 853     -   AMG 951     -   Amiodarone HCl Injection (Amiodarone HCl Injection)     -   Amobarbital Sodium Injection (Amytal Sodium)     -   Amytal Sodium (Amobarbital Sodium Injection)     -   Anakinra     -   Anti-Abeta     -   Anti-Beta7     -   Anti-Beta20     -   Anti-CD4     -   Anti-CD20     -   Anti-CD40     -   Anti-IFNalpha     -   Anti-IL13     -   Anti-OX40L     -   Anti-oxLDS     -   Anti-NGF     -   Anti-NRP1     -   Arixtra     -   Amphadase (Hyaluronidase Inj)     -   Ammonul (Sodium Phenylacetate and Sodium Benzoate Injection)     -   Anaprox     -   Anzemet Injection (Dolasetron Mesylate Injection)     -   Apidra (Insulin Glulisine [rDNA origin] Inj)     -   Apomab     -   Aranesp (darbepoetin alfa)     -   Argatroban (Argatroban Injection)     -   Arginine Hydrochloride Injection (R-Gene 10     -   Aristocort     -   Aristospan     -   Arsenic Trioxide Injection (Trisenox)     -   Articane HCl and Epinephrine Injection (Septocaine)     -   Arzerra (Ofatumumab Injection)     -   Asclera (Polidocanol Injection)     -   Ataluren     -   Ataluren-DMD     -   Atenolol Inj (Tenormin I.V. Injection)     -   Atracurium Besylate Injection (Atracurium Besylate Injection)     -   Avastin     -   Azactam Injection (Aztreonam Injection)     -   Azithromycin (Zithromax Injection)     -   Aztreonam Injection (Azactam Injection)     -   Baclofen Injection (Lioresal Intrathecal)     -   Bacteriostatic Water (Bacteriostatic Water for Injection)     -   Baclofen Injection (Lioresal Intrathecal)     -   Bal in Oil Ampules (Dimercarprol Injection)     -   BayHepB     -   BayTet     -   Benadryl     -   Bendamustine Hydrochloride Injection (Treanda)     -   Benztropine Mesylate Injection (Cogentin)     -   Betamethasone Injectable Suspension (Celestone Soluspan)     -   Bexxar     -   Bicillin C-R 900/300 (Penicillin G Benzathine and Penicillin G         Procaine Injection)     -   Blenoxane (Bleomycin Sulfate Injection)     -   Bleomycin Sulfate Injection (Blenoxane)     -   Boniva Injection (Ibandronate Sodium Injection)     -   Botox Cosmetic (OnabotulinumtoxinA for Injection)     -   BR3-FC     -   Bravelle (Urofollitropin Injection)     -   Bretylium (Bretylium Tosylate Injection)     -   Brevital Sodium (Methohexital Sodium for Injection)     -   Brethine     -   Briobacept     -   BTT-1023     -   Bupivacaine HCl     -   Byetta     -   Ca-DTPA (Pentetate Calcium Trisodium Inj)     -   Cabazitaxel Injection (Jevtana)     -   Caffeine Alkaloid (Caffeine and Sodium Benzoate Injection)     -   Calcijex Injection (Calcitrol)     -   Calcitrol (Calcijex Injection)     -   Calcium Chloride (Calcium Chloride Injection 10%)     -   Calcium Disodium Versenate (Edetate Calcium Disodium Injection)     -   Campath (Altemtuzumab)     -   Camptosar Injection (Irinotecan Hydrochloride)     -   Canakinumab Injection (Ilaris)     -   Capastat Sulfate (Capreomycin for Injection)     -   Capreomycin for Injection (Capastat Sulfate)     -   Cardiolite (Prep kit for Technetium Tc99 Sestamibi for         Injection)     -   Carticel     -   Cathflo     -   Cefazolin and Dextrose for Injection (Cefazolin Injection)     -   Cefepime Hydrochloride     -   Cefotaxime     -   Ceftriaxone     -   Cerezyme     -   Carnitor Injection     -   Caverject     -   Celestone Soluspan     -   Celsior     -   Cerebyx (Fosphenytoin Sodium Injection)     -   Ceredase (Alglucerase Injection)     -   Ceretec (Technetium Tc99m Exametazime Injection)     -   Certolizumab     -   CF-101     -   Chloramphenicol Sodium Succinate (Chloramphenicol Sodium         Succinate Injection)     -   Chloramphenicol Sodium Succinate Injection (Chloramphenicol         Sodium Succinate)     -   Cholestagel (Colesevelam HCL)     -   Choriogonadotropin Alfa Injection (Ovidrel)     -   Cimzia     -   Cisplatin (Cisplatin Injection)     -   Clolar (Clofarabine Injection)     -   Clomiphine Citrate     -   Clonidine Injection (Duraclon)     -   Cogentin (Benztropine Mesylate Injection)     -   Colistimethate Injection (Coly-Mycin M)     -   Coly-Mycin M (Colistimethate Injection)     -   Compath     -   Conivaptan Hcl Injection (Vaprisol)     -   Conjugated Estrogens for Injection (Premarin Injection)     -   Copaxone     -   Corticorelin Ovine Triflutate for Injection (Acthrel)     -   Corvert (Ibutilide Fumarate Injection)     -   Cubicin (Daptomycin Injection)     -   CF-101     -   Cyanokit (Hydroxocobalamin for Injection)     -   Cytarabine Liposome Injection (DepoCyt)     -   Cyanocobalamin     -   Cytovene (ganciclovir)     -   D.H.E. 45     -   Dacetuzumab     -   Dacogen (Decitabine Injection)     -   Dalteparin     -   Dantrium IV (Dantrolene Sodium for Injection)     -   Dantrolene Sodium for Injection (Dantrium IV)     -   Daptomycin Injection (Cubicin)     -   Darbepoietin Alfa     -   DDAVP Injection (Desmopressin Acetate Injection)     -   Decavax     -   Decitabine Injection (Dacogen)     -   Dehydrated Alcohol (Dehydrated Alcohol Injection)     -   Denosumab Injection (Prolia)     -   Delatestryl     -   Delestrogen     -   Delteparin Sodium     -   Depacon (Valproate Sodium Injection)     -   Depo Medrol (Methylprednisolone Acetate Injectable Suspension)     -   DepoCyt (Cytarabine Liposome Injection)     -   DepoDur (Morphine Sulfate XR Liposome Injection)     -   Desmopressin Acetate Injection (DDAVP Injection)     -   Depo-Estradiol     -   Depo-Provera 104 mg/ml     -   Depo-Provera 150 mg/ml     -   Depo-Testosterone     -   Dexrazoxane for Injection, Intravenous Infusion Only (Totect)     -   Dextrose/Electrolytes     -   Dextrose and Sodium Chloride Inj (Dextrose 5% in 0.9% Sodium         Chloride)     -   Dextrose     -   Diazepam Injection (Diazepam Injection)     -   Digoxin Injection (Lanoxin Injection)     -   Dilaudid-HP (Hydromorphone Hydrochloride Injection)     -   Dimercarprol Injection (Bal in Oil Ampules)     -   Diphenhydramine Injection (Benadryl Injection)     -   Dipyridamole Injection (Dipyridamole Injection)     -   DMOAD     -   Docetaxel for Injection (Taxotere)     -   Dolasetron Mesylate Injection (Anzemet Injection)     -   Doribax (Doripenem for Injection)     -   Doripenem for Injection (Doribax)     -   Doxercalciferol Injection (Hectorol Injection)     -   Doxil (Doxorubicin Hcl Liposome Injection)     -   Doxorubicin Hcl Liposome Injection (Doxil)     -   Duraclon (Clonidine Injection)     -   Duramorph (Morphine Injection)     -   Dysport (Abobotulinumtoxin A Injection)     -   Ecallantide Injection (Kalbitor)     -   EC-Naprosyn (naproxen)     -   Edetate Calcium Disodium Injection (Calcium Disodium Versenate)     -   Edex (Alprostadil for Injection)     -   Engerix     -   Edrophonium Injection (Enlon)     -   Eliglustat Tartate     -   Eloxatin (Oxaliplatin Injection)     -   Emend Injection (Fosaprepitant Dimeglumine Injection)     -   Enalaprilat Injection (Enalaprilat Injection)     -   Enlon (Edrophonium Injection)     -   Enoxaparin Sodium Injection (Lovenox)     -   Eovist (Gadoxetate Disodium Injection)     -   Enbrel (etanercept)     -   Enoxaparin     -   Epicel     -   Epinepherine     -   Epipen     -   Epipen Jr.     -   Epratuzumab     -   Erbitux     -   Ertapenem Injection (Invanz)     -   Erythropoieten     -   Essential Amino Acid Injection (Nephramine)     -   Estradiol Cypionate     -   Estradiol Valerate     -   Etanercept     -   Exenatide Injection (Byetta)     -   Evlotra     -   Fabrazyme (Adalsidase beta)     -   Famotidine Injection     -   FDG (Fludeoxyglucose F 18 Injection)     -   Feraheme (Ferumoxytol Injection)     -   Feridex I.V. (Ferumoxides Injectable Solution)     -   Fertinex     -   Ferumoxides Injectable Solution (Feridex I.V.)     -   Ferumoxytol Injection (Feraheme)     -   Flagyl Injection (Metronidazole Injection)     -   Fluarix     -   Fludara (Fludarabine Phosphate)     -   Fludeoxyglucose F 18 Injection (FDG)     -   Fluorescein Injection (Ak-Fluor)     -   Follistim AQ Cartridge (Follitropin Beta Injection)     -   Follitropin Alfa Injection (Gonal-f RFF)     -   Follitropin Beta Injection (Follistim AQ Cartridge)     -   Folotyn (Pralatrexate Solution for Intravenous Injection)     -   Fondaparinux     -   Forteo (Teriparatide (rDNA origin) Injection)     -   Fostamatinib     -   Fosaprepitant Dimeglumine Injection (Emend Injection)     -   Foscarnet Sodium Injection (Foscavir)     -   Foscavir (Foscarnet Sodium Injection)     -   Fosphenytoin Sodium Injection (Cerebyx)     -   Fospropofol Disodium Injection (Lusedra)     -   Fragmin     -   Fuzeon (enfuvirtide)     -   GA101     -   Gadobenate Dimeglumine Injection (Multihance)     -   Gadofosveset Trisodium Injection (Ablavar)     -   Gadoteridol Injection Solution (ProHance)     -   Gadoversetamide Injection (OptiMARK)     -   Gadoxetate Disodium Injection (Eovist)     -   Ganirelix (Ganirelix Acetate Injection)     -   Gardasil     -   GC₁₀₀₈     -   GDFD     -   Gemtuzumab Ozogamicin for Injection (Mylotarg)     -   Genotropin     -   Gentamicin Injection     -   GENZ-112638     -   Golimumab Injection (Simponi Injection)     -   Gonal-f RFF (Follitropin Alfa Injection)     -   Granisetron Hydrochloride (Kytril Injection)     -   Gentamicin Sulfate     -   Glatiramer Acetate     -   Glucagen     -   Glucagon     -   HAE1     -   Haldol (Haloperidol Injection)     -   Havrix     -   Hectorol Injection (Doxercalciferol Injection)     -   Hedgehog Pathway Inhibitor     -   Heparin     -   Herceptin     -   hG-CSF     -   Humalog     -   Human Growth Hormone     -   Humatrope     -   HuMax     -   Humegon     -   Humira     -   Humulin     -   Ibandronate Sodium Injection (Boniva Injection)     -   Ibuprofen Lysine Injection (NeoProfen)     -   Ibutilide Fumarate Injection (Corvert)     -   Idamycin PFS (Idarubicin Hydrochloride Injection)     -   Idarubicin Hydrochloride Injection (Idamycin PFS)     -   Ilaris (Canakinumab Injection)     -   Imipenem and Cilastatin for Injection (Primaxin I.V.)     -   Imitrex     -   Incobotulinumtoxin A for Injection (Xeomin)     -   Increlex (Mecasermin [rDNA origin] Injection)     -   Indocin IV (Indomethacin Inj)     -   Indomethacin Inj (Indocin IV)     -   Infanrix     -   Innohep     -   Insulin     -   Insulin Aspart [rDNA origin] Inj (NovoLog)     -   Insulin Glargine [rDNA origin] Injection (Lantus)     -   Insulin Glulisine [rDNA origin] Inj (Apidra)     -   Interferon alfa-2b, Recombinant for Injection (Intron A)     -   Intron A (Interferon alfa-2b, Recombinant for Injection)     -   Invanz (Ertapenem Injection)     -   Invega Sustenna (Paliperidone Palmitate Extended-Release         Injectable Suspension)     -   Invirase (saquinavir mesylate)     -   Iobenguane 1123 Injection for Intravenous Use (AdreView)     -   Iopromide Injection (Ultravist)     -   Ioversol Injection (Optiray Injection)     -   Iplex (Mecasermin Rinfabate [rDNA origin] Injection)     -   Iprivask     -   Irinotecan Hydrochloride (Camptosar Injection)     -   Iron Sucrose Injection (Venofer)     -   Istodax (Romidepsin for Injection)     -   Itraconazole Injection (Sporanox Injection)     -   Jevtana (Cabazitaxel Injection)     -   Jonexa     -   Kalbitor (Ecallantide Injection)     -   KCL in D5NS (Potassium Chloride in 5% Dextrose and Sodium         Chloride Injection)     -   KCL in D5W     -   KCL in NS     -   Kenalog 10 Injection (Triamcinolone Acetonide Injectable         Suspension)     -   Kepivance (Palifermin)     -   Keppra Injection (Levetiracetam)     -   Keratinocyte     -   KFG     -   Kinase Inhibitor     -   Kineret (Anakinra)     -   Kinlytic (Urokinase Injection)     -   Kinrix     -   Klonopin (clonazepam)     -   Kytril Injection (Granisetron Hydrochloride)     -   lacosamide Tablet and Injection (Vimpat)     -   Lactated Ringer's     -   Lanoxin Injection (Digoxin Injection)     -   Lansoprazole for Injection (Prevacid I.V.)     -   Lantus     -   Leucovorin Calcium (Leucovorin Calcium Injection)     -   Lente (L)     -   Leptin     -   Levemir     -   Leukine Sargramostim     -   Leuprolide Acetate     -   Levothyroxine     -   Levetiracetam (Keppra Injection)     -   Lovenox     -   Levocarnitine Injection (Carnitor Injection)     -   Lexiscan (Regadenoson Injection)     -   Lioresal Intrathecal (Baclofen Injection)     -   Liraglutide [rDNA] Injection (Victoza)     -   Lovenox (Enoxaparin Sodium Injection)     -   Lucentis (Ranibizumab Injection)     -   Lumizyme     -   Lupron (Leuprolide Acetate Injection)     -   Lusedra (Fospropofol Disodium Injection)     -   Maci     -   Magnesium Sulfate (Magnesium Sulfate Injection)     -   Mannitol Injection (Mannitol IV)     -   Marcaine (Bupivacaine Hydrochloride and Epinephrine Injection)     -   Maxipime (Cefepime Hydrochloride for Injection)     -   MDP Multidose Kit of Technetium Injection (Technetium Tc99m         Medronate Injection)     -   Mecasermin [rDNA origin] Injection (Increlex)     -   Mecasermin Rinfabate [rDNA origin] Injection (Iplex)     -   Melphalan Hcl Injection (Alkeran Injection)     -   Methotrexate     -   Menactra     -   Menopur (Menotropins Injection)     -   Menotropins for Injection (Repronex)     -   Methohexital Sodium for Injection (Brevital Sodium)     -   Methyldopate Hydrochloride Injection, Solution (Methyldopate         Hcl)     -   Methylene Blue (Methylene Blue Injection)     -   Methylprednisolone Acetate Injectable Suspension (Depo Medrol)     -   MetMab     -   Metoclopramide Injection (Reglan Injection)     -   Metrodin (Urofollitropin for Injection)     -   Metronidazole Injection (Flagyl Injection)     -   Miacalcin     -   Midazolam (Midazolam Injection)     -   Mimpara (Cinacalet)     -   Minocin Injection (Minocycline Inj)     -   Minocycline Inj (Minocin Injection)     -   Mipomersen     -   Mitoxantrone for Injection Concentrate (Novantrone)     -   Morphine Injection (Duramorph)     -   Morphine Sulfate XR Liposome Injection (DepoDur)     -   Morrhuate Sodium (Morrhuate Sodium Injection)     -   Motesanib     -   Mozobil (Plerixafor Injection)     -   Multihance (Gadobenate Dimeglumine Injection)     -   Multiple Electrolytes and Dextrose Injection     -   Multiple Electrolytes Injection     -   Mylotarg (Gemtuzumab Ozogamicin for Injection)     -   Myozyme (Alglucosidase alfa)     -   Nafcillin Injection (Nafcillin Sodium)     -   Nafcillin Sodium (Nafcillin Injection)     -   Naltrexone XR Inj (Vivitrol)     -   Naprosyn (naproxen)     -   NeoProfen (Ibuprofen Lysine Injection)     -   Nandrol Decanoate     -   Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection)     -   NEO-GAA     -   NeoTect (Technetium Tc 99m Depreotide Injection)     -   Nephramine (Essential Amino Acid Injection)     -   Neulasta (pegfilgrastim)     -   Neupogen (Filgrastim)     -   Novolin     -   Novolog     -   NeoRecormon     -   Neutrexin (Trimetrexate Glucuronate Inj)     -   NPH (N)     -   Nexterone (Amiodarone HCl Injection)     -   Norditropin (Somatropin Injection)     -   Normal Saline (Sodium Chloride Injection)     -   Novantrone (Mitoxantrone for Injection Concentrate)     -   Novolin 70/30 Innolet (70% NPH, Human Insulin Isophane         Suspension and 30% Regular, Human Insulin Injection)     -   NovoLog (Insulin Aspart [rDNA origin] Inj)     -   Nplate (romiplostim)     -   Nutropin (Somatropin (rDNA origin) for Inj)     -   Nutropin AQ     -   Nutropin Depot (Somatropin (rDNA origin) for Inj)     -   Octreotide Acetate Injection (Sandostatin LAR)     -   Ocrelizumab     -   Ofatumumab Injection (Arzerra)     -   Olanzapine Extended Release Injectable Suspension (Zyprexa         Relprevv)     -   Omnitarg     -   Omnitrope (Somatropin [ rDNA origin] Injection)     -   Ondansetron Hydrochloride Injection (Zofran Injection)     -   OptiMARK (Gadoversetamide Injection)     -   Optiray Injection (Ioversol Injection)     -   Orencia     -   Osmitrol Injection in Aviva (Mannitol Injection in Aviva Plastic         Pharmaceutical package 210)     -   Osmitrol Injection in Viaflex (Mannitol Injection in Viaflex         Plastic Pharmaceutical package 210)     -   Osteoprotegrin     -   Ovidrel (Choriogonadotropin Alfa Injection)     -   Oxacillin (Oxacillin for Injection)     -   Oxaliplatin Injection (Eloxatin)     -   Oxytocin Injection (Pitocin)     -   Paliperidone Palmitate Extended-Release Injectable Suspension         (Invega Sustenna)     -   Pamidronate Disodium Injection (Pamidronate Disodium Injection)     -   Panitumumab Injection for Intravenous Use (Vectibix)     -   Papaverine Hydrochloride Injection (Papaverine Injection)     -   Papaverine Injection (Papaverine Hydrochloride Injection)     -   Parathyroid Hormone     -   Paricalcitol Injection Fliptop Vial (Zemplar Injection)     -   PARP Inhibitor     -   Pediarix     -   PEGIntron     -   Peginterferon     -   Pegfilgrastim     -   Penicillin G Benzathine and Penicillin G Procaine     -   Pentetate Calcium Trisodium Inj (Ca-DTPA)     -   Pentetate Zinc Trisodium Injection (Zn-DTPA)     -   Pepcid Injection (Famotidine Injection)     -   Pergonal     -   Pertuzumab     -   Phentolamine Mesylate (Phentolamine Mesylate for Injection)     -   Physostigmine Salicylate (Physostigmine Salicylate (injection))     -   Physostigmine Salicylate (injection) (Physostigmine Salicylate)     -   Piperacillin and Tazobactam Injection (Zosyn)     -   Pitocin (Oxytocin Injection)     -   Plasma-Lyte 148 (Multiple Electrolytes Inj)     -   Plasma-Lyte 56 and Dextrose (Multiple Electrolytes and Dextrose         Injection in Viaflex Plastic Pharmaceutical package 210)     -   PlasmaLyte     -   Plerixafor Injection (Mozobil)     -   Polidocanol Injection (Asclera)     -   Potassium Chloride     -   Pralatrexate Solution for Intravenous Injection (Folotyn)     -   Pramlintide Acetate Injection (Symlin)     -   Premarin Injection (Conjugated Estrogens for Injection)     -   Prep kit for Technetium Tc99 Sestamibi for Injection         (Cardiolite)     -   Prevacid I.V. (Lansoprazole for Injection)     -   Primaxin I.V. (Imipenem and Cilastatin for Injection)     -   Prochymal     -   Procrit     -   Progesterone     -   ProHance (Gadoteridol Injection Solution)     -   Prolia (Denosumab Injection)     -   Promethazine HCl Injection (Promethazine Hydrochloride         Injection)     -   Propranolol Hydrochloride Injection (Propranolol Hydrochloride         Injection)     -   Quinidine Gluconate Injection (Quinidine Injection)     -   Quinidine Injection (Quinidine Gluconate Injection)     -   R-Gene 10 (Arginine Hydrochloride Injection)     -   Ranibizumab Injection (Lucentis)     -   Ranitidine Hydrochloride Injection (Zantac Injection)     -   Raptiva     -   Reclast (Zoledronic Acid Injection)     -   Recombivarix HB     -   Regadenoson Injection (Lexiscan)     -   Reglan Injection (Metoclopramide Injection)     -   Remicade     -   Renagel     -   Renvela (Sevelamer Carbonate)     -   Repronex (Menotropins for Injection)     -   Retrovir IV (Zidovudine Injection)     -   rhApo2L/TRAIL     -   Ringer's and 5% Dextrose Injection (Ringers in Dextrose)     -   Ringer's Injection (Ringers Injection)     -   Rituxan     -   Rituximab     -   Rocephin (ceftriaxone)     -   Rocuronium Bromide Injection (Zemuron)     -   Roferon-A (interferon alfa-2a)     -   Romazicon (flumazenil)     -   Romidepsin for Injection (Istodax)     -   Saizen (Somatropin Injection)     -   Sandostatin LAR (Octreotide Acetate Injection)     -   Sclerostin Ab     -   Sensipar (cinacalcet)     -   Sensorcaine (Bupivacaine HCl Injections)     -   Septocaine (Articane HCl and Epinephrine Injection)     -   Serostim LQ (Somatropin (rDNA origin) Injection)     -   Simponi Injection (Golimumab Injection)     -   Sodium Acetate (Sodium Acetate Injection)     -   Sodium Bicarbonate (Sodium Bicarbonate 5% Injection)     -   Sodium Lactate (Sodium Lactate Injection in AVIVA)     -   Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul)     -   Somatropin (rDNA origin) for Inj (Nutropin)     -   Sporanox Injection (Itraconazole Injection)     -   Stelara Injection (Ustekinumab)     -   Stemgen     -   Sufenta (Sufentanil Citrate Injection)     -   Sufentanil Citrate Injection (Sufenta)     -   Sumavel     -   Sumatriptan Injection (Alsuma)     -   Symlin     -   Symlin Pen     -   Systemic Hedgehog Antagonist     -   Synvisc-One (Hylan G-F 20 Single Intra-articular Injection)     -   Tarceva     -   Taxotere (Docetaxel for Injection)     -   Technetium Tc 99m     -   Telavancin for Injection (Vibativ)     -   Temsirolimus Injection (Torisel)     -   Tenormin I.V. Injection (Atenolol Inj)     -   Teriparatide (rDNA origin) Injection (Forteo)     -   Testosterone Cypionate     -   Testosterone Enanthate     -   Testosterone Propionate     -   Tev-Tropin (Somatropin, rDNA Origin, for Injection)     -   tgAAC₉₄     -   Thallous Chloride     -   Theophylline     -   Thiotepa (Thiotepa Injection)     -   Thymoglobulin (Anti-Thymocyte Globulin (Rabbit)     -   Thyrogen (Thyrotropin Alfa for Injection)     -   Ticarcillin Disodium and Clavulanate Potassium Galaxy (Timentin         Injection)     -   Tigan Injection (Trimethobenzamide Hydrochloride Injectable)     -   Timentin Injection (Ticarcillin Disodium and Clavulanate         Potassium Galaxy)     -   TNKase     -   Tobramycin Injection (Tobramycin Injection)     -   Tocilizumab Injection (Actemra)     -   Torisel (Temsirolimus Injection)     -   Totect (Dexrazoxane for Injection, Intravenous Infusion Only)     -   Trastuzumab-DM1     -   Travasol (Amino Acids (Injection))     -   Treanda (Bendamustine Hydrochloride Injection)     -   Trelstar (Triptorelin Pamoate for Injectable Suspension)     -   Triamcinolone Acetonide     -   Triamcinolone Diacetate     -   Triamcinolone Hexacetonide Injectable Suspension (Aristospan         Injection 20 mg)     -   Triesence (Triamcinolone Acetonide Injectable Suspension)     -   Trimethobenzamide Hydrochloride Injectable (Tigan Injection)     -   Trimetrexate Glucuronate Inj (Neutrexin)     -   Triptorelin Pamoate for Injectable Suspension (Trelstar)     -   Twinject     -   Trivaris (Triamcinolone Acetonide Injectable Suspension)     -   Trisenox (Arsenic Trioxide Injection)     -   Twinrix     -   Typhoid Vi     -   Ultravist (Iopromide Injection)     -   Urofollitropin for Injection (Metrodin)     -   Urokinase Injection (Kinlytic)     -   Ustekinumab (Stelara Injection)     -   Ultralente (U)     -   Valium (diazepam)     -   Valproate Sodium Injection (Depacon)     -   Valtropin (Somatropin Injection)     -   Vancomycin Hydrochloride (Vancomycin Hydrochloride Injection)     -   Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride)     -   Vaprisol (Conivaptan Hcl Injection)     -   VAQTA     -   Vasovist (Gadofosveset Trisodium Injection for Intravenous Use)     -   Vectibix (Panitumumab Injection for Intravenous Use)     -   Venofer (Iron Sucrose Injection)     -   Verteporfin Inj (Visudyne)     -   Vibativ (Telavancin for Injection)     -   Victoza (Liraglutide [rDNA] Injection)     -   Vimpat (lacosamide Tablet and Injection)     -   Vinblastine Sulfate (Vinblastine Sulfate Injection)     -   Vincasar PFS (Vincristine Sulfate Injection)     -   Victoza     -   Vincristine Sulfate (Vincristine Sulfate Injection)     -   Visudyne (Verteporfin Inj)     -   Vitamin B-12     -   Vivitrol (Naltrexone XR Inj)     -   Voluven (Hydroxyethyl Starch in Sodium Chloride Injection)     -   Xeloda     -   Xenical (orlistat)     -   Xeomin (Incobotulinumtoxin A for Injection)     -   Xolair     -   Zantac Injection (Ranitidine Hydrochloride Injection)     -   Zemplar Injection (Paricalcitol Injection Fliptop Vial)     -   Zemuron (Rocuronium Bromide Injection)     -   Zenapax (daclizumab)     -   Zevalin     -   Zidovudine Injection (Retrovir IV)     -   Zithromax Injection (Azithromycin)     -   Zn-DTPA (Pentetate Zinc Trisodium Injection)     -   Zofran Injection (Ondansetron Hydrochloride Injection)     -   Zingo     -   Zoledronic Acid for Inj (Zometa)     -   Zoledronic Acid Injection (Reclast)     -   Zometa (Zoledronic Acid for Inj)     -   Zosyn (Piperacillin and Tazobactam Injection)     -   Zyprexa Relprevv (Olanzapine Extended Release Injectable         Suspension)

Liquid Drugs (Non-Injectable)

-   -   Abilify     -   AccuNeb (Albuterol Sulfate Inhalation Solution)     -   Actidose Aqua (Activated Charcoal Suspension)     -   Activated Charcoal Suspension (Actidose Aqua)     -   Advair     -   Agenerase Oral Solution (Amprenavir Oral Solution)     -   Akten (Lidocaine Hydrochloride Ophthalmic Gel)     -   Alamast (Pemirolast Potassium Ophthalmic Solution)     -   Albumin (Human) 5% Solution (Buminate 5%)     -   Albuterol Sulfate Inhalation Solution     -   Alinia     -   Alocril     -   Alphagan     -   Alrex     -   Alvesco     -   Amprenavir Oral Solution     -   Analpram-HC     -   Arformoterol Tartrate Inhalation Solution (Brovana)     -   Aristospan Injection 20 mg (Triamcinolone Hexacetonide         Injectable Suspension)     -   Asacol     -   Asmanex     -   Astepro     -   Astepro (Azelastine Hydrochloride Nasal Spray)     -   Atrovent Nasal Spray (Ipratropium Bromide Nasal Spray)     -   Atrovent Nasal Spray 0.06     -   Augmentin ES-600     -   Azasite (Azithromycin Ophthalmic Solution)     -   Azelaic Acid (Finacea Gel)     -   Azelastine Hydrochloride Nasal Spray (Astepro)     -   Azelex (Azelaic Acid Cream)     -   Azopt (Brinzolamide Ophthalmic Suspension)     -   Bacteriostatic Saline     -   Balanced Salt     -   Bepotastine     -   Bactroban Nasal     -   Bactroban     -   Beclovent     -   Benzac W     -   Betimol     -   Betoptic S     -   Bepreve     -   Bimatoprost Ophthalmic Solution     -   Bleph 10 (Sulfacetamide Sodium Ophthalmic Solution 10%)     -   Brinzolamide Ophthalmic Suspension (Azopt)     -   Bromfenac Ophthalmic Solution (Xibrom)     -   Bromhist     -   Brovana (Arformoterol Tartrate Inhalation Solution)     -   Budesonide Inhalation Suspension (Pulmicort Respules)     -   Cambia (Diclofenac Potassium for Oral Solution)     -   Capex     -   Carac     -   Carboxine-PSE     -   Carnitor     -   Cayston (Aztreonam for Inhalation Solution)     -   Cellcept     -   Centany     -   Cerumenex     -   Ciloxan Ophthalmic Solution (Ciprofloxacin HCL Ophthalmic         Solution)     -   Ciprodex     -   Ciprofloxacin HCL Ophthalmic Solution (Ciloxan Ophthalmic         Solution)     -   Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)     -   CoLyte (PEG Electrolytes Solution)     -   Combiven     -   Comtan     -   Condylox     -   Cordran     -   Cortisporin Ophthalmic Suspension     -   Cortisporin Otic Suspension     -   Cromolyn Sodium Inhalation Solution (Intal Nebulizer Solution)     -   Cromolyn Sodium Ophthalmic Solution (Opticrom)     -   Crystalline Amino Acid Solution with Electrolytes (Aminosyn         Electrolytes)     -   Cutivate     -   Cuvposa (Glycopyrrolate Oral Solution)     -   Cyanocobalamin (CaloMist Nasal Spray)     -   Cyclosporine Oral Solution (Gengraf Oral Solution)     -   Cyclogyl     -   Cysview (Hexaminolevulinate Hydrochloride Intravesical Solution)     -   DermOtic Oil (Fluocinolone Acetonide Oil Ear Drops)     -   Desmopressin Acetate Nasal Spray     -   DDAVP     -   Derma-Smoothe/FS     -   Dexamethasone Intensol     -   Dianeal Low Calcium     -   Dianeal PD     -   Diclofenac Potassium for Oral Solution (Cambia)     -   Didanosine Pediatric Powder for Oral Solution (Videx)     -   Differin     -   Dilantin 125 (Phenytoin Oral Suspension)     -   Ditropan     -   Dorzolamide Hydrochloride Ophthalmic Solution (Trusopt)     -   Dorzolamide Hydrochloride-Timolol Maleate Ophthalmic Solution         (Cosopt)     -   Dovonex Scalp (Calcipotriene Solution)     -   Doxycycline Calcium Oral Suspension (Vibramycin Oral)     -   Efudex     -   Elaprase (Idursulfase Solution)     -   Elestat (Epinastine HCl Ophthalmic Solution)     -   Elocon     -   Epinastine HCl Ophthalmic Solution (Elestat)     -   Epivir HBV     -   Epogen (Epoetin alfa)     -   Erythromycin Topical Solution 1.5% (Staticin)     -   Ethiodol (Ethiodized Oil)     -   Ethosuximide Oral Solution (Zarontin Oral Solution)     -   Eurax     -   Extraneal (Icodextrin Peritoneal Dialysis Solution)     -   Felbatol     -   Feridex I.V. (Ferumoxides Injectable Solution)     -   Flovent     -   Floxin Otic (Ofloxacin Otic Solution)     -   Flo-Pred (Prednisolone Acetate Oral Suspension)     -   Fluoroplex     -   Flunisolide Nasal Solution (Flunisolide Nasal Spray 0.025%)     -   Fluorometholone Ophthalmic Suspension (FML)     -   Flurbiprofen Sodium Ophthalmic Solution (Ocufen)     -   FML     -   Foradil     -   Formoterol Fumarate Inhalation Solution (Perforomist)     -   Fosamax     -   Furadantin (Nitrofurantoin Oral Suspension)     -   Furoxone     -   Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)     -   Gantrisin (Acetyl Sulfisoxazole Pediatric Suspension)     -   Gatifloxacin Ophthalmic Solution (Zymar)     -   Gengraf Oral Solution (Cyclosporine Oral Solution)     -   Glycopyrrolate Oral Solution (Cuvposa)     -   Halcinonide Topical Solution (Halog Solution)     -   Halog Solution (Halcinonide Topical Solution)     -   HEP-LOCK U/P (Preservative-Free Heparin Lock Flush Solution)     -   Heparin Lock Flush Solution (Hepflush 10     -   Hexaminolevulinate Hydrochloride Intravesical Solution (Cysview)     -   Hydrocodone Bitartrate and Acetaminophen Oral Solution (Lortab         Elixir)     -   Hydroquinone 3% Topical Solution (Melquin-3 Topical Solution)     -   IAP Antagonist     -   Isopto     -   Ipratropium Bromide Nasal Spray (Atrovent Nasal Spray)     -   Itraconazole Oral Solution (Sporanox Oral Solution)     -   Ketorolac Tromethamine Ophthalmic Solution (Acular LS)     -   Kaletra     -   Lanoxin     -   Lexiva     -   Leuprolide Acetate for Depot Suspension (Lupron Depot 11.25 mg)     -   Levobetaxolol Hydrochloride Ophthalmic Suspension (Betaxon)     -   Levocarnitine Tablets, Oral Solution, Sugar-Free (Carnitor)     -   Levofloxacin Ophthalmic Solution 0.5% (Quixin)     -   Lidocaine HCl Sterile Solution (Xylocaine MPF Sterile Solution)     -   Lok Pak (Heparin Lock Flush Solution)     -   Lorazepam Intensol     -   Lortab Elixir (Hydrocodone Bitartrate and Acetaminophen Oral         Solution)     -   Lotemax (Loteprednol Etabonate Ophthalmic Suspension)     -   Loteprednol Etabonate Ophthalmic Suspension (Alrex)     -   Low Calcium Peritoneal Dialysis Solutions (Dianeal Low Calcium)     -   Lumigan (Bimatoprost Ophthalmic Solution 0.03% for Glaucoma)     -   Lupron Depot 11.25 mg (Leuprolide Acetate for Depot Suspension)     -   Megestrol Acetate Oral Suspension (Megestrol Acetate Oral         Suspension)     -   MEK Inhibitor     -   Mepron     -   Mesnex     -   Mestinon     -   Mesalamine Rectal Suspension Enema (Rowasa)     -   Melquin-3 Topical Solution (Hydroquinone 3% Topical Solution)     -   MetMab     -   Methyldopate Hcl (Methyldopate Hydrochloride Injection,         Solution)     -   Methylin Oral Solution (Methylphenidate HCl Oral Solution 5 mg/5         mL and 10 mg/5 mL)     -   Methylprednisolone Acetate Injectable Suspension (Depo Medrol)     -   Methylphenidate HCl Oral Solution 5 mg/5 mL and 10 mg/5 mL         (Methylin Oral Solution)     -   Methylprednisolone sodium succinate (Solu Medrol)     -   Metipranolol Ophthalmic Solution (Optipranolol)     -   Migranal     -   Miochol-E (Acetylcholine Chloride Intraocular Solution)     -   Micro-K for Liquid Suspension (Potassium Chloride Extended         Release Formulation for Liquid Suspension)     -   Minocin (Minocycline Hydrochloride Oral Suspension)     -   Nasacort     -   Neomycin and Polymyxin B Sulfates and Hydrocortisone     -   Nepafenac Ophthalmic Suspension (Nevanac)     -   Nevanac (Nepafenac Ophthalmic Suspension)     -   Nitrofurantoin Oral Suspension (Furadantin)     -   Noxafil (Posaconazole Oral Suspension)     -   Nystatin (oral) (Nystatin Oral Suspension)     -   Nystatin Oral Suspension (Nystatin (oral))     -   Ocufen (Flurbiprofen Sodium Ophthalmic Solution)     -   Ofloxacin Ophthalmic Solution (Ofloxacin Ophthalmic Solution)     -   Ofloxacin Otic Solution (Floxin Otic)     -   Olopatadine Hydrochloride Ophthalmic Solution (Pataday)     -   Opticrom (Cromolyn Sodium Ophthalmic Solution)     -   Optipranolol (Metipranolol Ophthalmic Solution)     -   Patanol     -   Pediapred     -   PerioGard     -   Phenytoin Oral Suspension (Dilantin 125)     -   Phisohex     -   Posaconazole Oral Suspension (Noxafil)     -   Potassium Chloride Extended Release Formulation for Liquid         Suspension (Micro-K for Liquid Suspension)     -   Pataday (Olopatadine Hydrochloride Ophthalmic Solution)     -   Patanase Nasal Spray (Olopatadine Hydrochloride Nasal Spray)     -   PEG Electrolytes Solution (CoLyte)     -   Pemirolast Potassium Ophthalmic Solution (Alamast)     -   Penlac (Ciclopirox Topical Solution)     -   PENNSAID (Diclofenac Sodium Topical Solution)     -   Perforomist (Formoterol Fumarate Inhalation Solution)     -   Peritoneal Dialysis Solution     -   Phenylephrine Hydrochloride Ophthalmic Solution (Neo-Synephrine)     -   Phospholine Iodide (Echothiophate Iodide for Ophthalmic         Solution)     -   Podofilox (Podofilox Topical Solution)     -   Pred Forte (Prednisolone Acetate Ophthalmic Suspension)     -   Pralatrexate Solution for Intravenous Injection (Folotyn)     -   Pred Mild     -   Prednisone Intensol     -   Prednisolone Acetate Ophthalmic Suspension (Pred Forte)     -   Prevacid     -   PrismaSol Solution (Sterile Hemofiltration Hemodiafiltration         Solution)     -   ProAir     -   Proglycem     -   ProHance (Gadoteridol Injection Solution)     -   Proparacaine Hydrochloride Ophthalmic Solution (Alcaine)     -   Propine     -   Pulmicort     -   Pulmozyme     -   Quixin (Levofloxacin Ophthalmic Solution 0.5%)     -   QVAR     -   Rapamune     -   Rebetol     -   Relacon-HC     -   Rotarix (Rotavirus Vaccine, Live, Oral Suspension)     -   Rotavirus Vaccine, Live, Oral Suspension (Rotarix)     -   Rowasa (Mesalamine Rectal Suspension Enema)     -   Sabril (Vigabatrin Oral Solution)     -   Sacrosidase Oral Solution (Sucraid)     -   Sandimmune     -   Sepra     -   Serevent Diskus     -   Solu Cortef (Hydrocortisone Sodium Succinate)     -   Solu Medrol (Methylprednisolone sodium succinate)     -   Spiriva     -   Sporanox Oral Solution (Itraconazole Oral Solution)     -   Staticin (Erythromycin Topical Solution 1.5%)     -   Stalevo     -   Starlix     -   Sterile Hemofiltration Hemodiafiltration Solution (PrismaSol         Solution)     -   Stimate     -   Sucralfate (Carafate Suspension)     -   Sulfacetamide Sodium Ophthalmic Solution 10% (Bleph 10     -   Synarel Nasal Solution (Nafarelin Acetate Nasal Solution for         Endometriosis)     -   Taclonex Scalp (Calcipotriene and Betamethasone Dipropionate         Topical Suspension)     -   Tamiflu     -   Tobi     -   TobraDex     -   Tobradex ST (Tobramycin/Dexamethasone Ophthalmic Suspension         0.3%/0.05%)     -   Tobramycin/Dexamethasone Ophthalmic Suspension 0.3%/0.05%         (Tobradex ST)     -   Timolol     -   Timoptic     -   Travatan Z     -   Treprostinil Inhalation Solution (Tyvaso)     -   Trusopt (Dorzolamide Hydrochloride Ophthalmic Solution)     -   Tyvaso (Treprostinil Inhalation Solution)     -   Ventolin     -   Vfend     -   Vibramycin Oral (Doxycycline Calcium Oral Suspension)     -   Videx (Didanosine Pediatric Powder for Oral Solution)     -   Vigabatrin Oral Solution (Sabril)     -   Viokase     -   Viracept     -   Viramune     -   Vitamin K1 (Fluid Colloidal Solution of Vitamin K1)     -   Voltaren Ophthalmic (Diclofenac Sodium Ophthalmic Solution)     -   Zarontin Oral Solution (Ethosuximide Oral Solution)     -   Ziagen     -   Zyvox     -   Zymar (Gatifloxacin Ophthalmic Solution)     -   Zymaxid (Gatifloxacin Ophthalmic Solution)

Drug Classes

-   -   5-alpha-reductase inhibitors     -   5-aminosalicylates     -   5HT3 receptor antagonists     -   adamantane antivirals     -   adrenal cortical steroids     -   adrenal corticosteroid inhibitors     -   adrenergic bronchodilators     -   agents for hypertensive emergencies     -   agents for pulmonary hypertension     -   aldosterone receptor antagonists     -   alkylating agents     -   alpha-adrenoreceptor antagonists     -   alpha-glucosidase inhibitors     -   alternative medicines     -   amebicides     -   aminoglycosides     -   aminopenicillins     -   aminosalicylates     -   amylin analogs     -   Analgesic Combinations     -   Analgesics     -   androgens and anabolic steroids     -   angiotensin converting enzyme inhibitors     -   angiotensin II inhibitors     -   anorectal preparations     -   anorexiants     -   antacids     -   anthelmintics     -   anti-angiogenic ophthalmic agents     -   anti-CTLA-4 monoclonal antibodies     -   anti-infectives     -   antiadrenergic agents, centrally acting     -   antiadrenergic agents, peripherally acting     -   antiandrogens     -   antianginal agents     -   antiarrhythmic agents     -   antiasthmatic combinations     -   antibiotics/antineoplastics     -   anticholinergic antiemetics     -   anticholinergic antiparkinson agents     -   anticholinergic bronchodilators     -   anticholinergic chronotropic agents     -   anticholinergics/antispasmodics     -   anticoagulants     -   anticonvulsants     -   antidepressants     -   antidiabetic agents     -   antidiabetic combinations     -   antidiarrheals     -   antidiuretic hormones     -   antidotes     -   antiemetic/antivertigo agents     -   antifungals     -   antigonadotropic agents     -   antigout agents     -   antihistamines     -   antihyperlipidemic agents     -   antihyperlipidemic combinations     -   antihypertensive combinations     -   antihyperuricemic agents     -   antimalarial agents     -   antimalarial combinations     -   antimalarial quinolines     -   antimetabolites     -   antimigraine agents     -   antineoplastic detoxifying agents     -   antineoplastic interferons     -   antineoplastic monoclonal antibodies     -   antineoplastics     -   antiparkinson agents     -   antiplatelet agents     -   antipseudomonal penicillins     -   antipsoriatics     -   antipsychotics     -   antirheumatics     -   antiseptic and germicides     -   antithyroid agents     -   antitoxins and antivenins     -   antituberculosis agents     -   antituberculosis combinations     -   antitussives     -   antiviral agents     -   antiviral combinations     -   antiviral interferons     -   anxiolytics, sedatives, and hypnotics     -   aromatase inhibitors     -   atypical antipsychotics     -   azole antifungals     -   bacterial vaccines     -   barbiturate anticonvulsants     -   barbiturates     -   BCR-ABL tyrosine kinase inhibitors     -   benzodiazepine anticonvulsants     -   benzodiazepines     -   beta-adrenergic blocking agents     -   beta-lactamase inhibitors     -   bile acid sequestrants     -   biologicals     -   bisphosphonates     -   bone resorption inhibitors     -   bronchodilator combinations     -   bronchodilators     -   calcitonin     -   calcium channel blocking agents     -   carbamate anticonvulsants     -   carbapenems     -   carbonic anhydrase inhibitor anticonvulsants     -   carbonic anhydrase inhibitors     -   cardiac stressing agents     -   cardioselective beta blockers     -   cardiovascular agents     -   catecholamines     -   CD20 monoclonal antibodies     -   CD33 monoclonal antibodies     -   CD52 monoclonal antibodies     -   central nervous system agents     -   cephalosporins     -   cerumenolytics     -   chelating agents     -   chemokine receptor antagonist     -   chloride channel activators     -   cholesterol absorption inhibitors     -   cholinergic agonists     -   cholinergic muscle stimulants     -   cholinesterase inhibitors     -   CNS stimulants     -   coagulation modifiers     -   colony stimulating factors     -   contraceptives     -   corticotropin     -   coumarins and indandiones     -   cox-2 inhibitors     -   decongestants     -   dermatological agents     -   diagnostic radiopharmaceuticals     -   dibenzazepine anticonvulsants     -   digestive enzymes     -   dipeptidyl peptidase 4 inhibitors     -   diuretics     -   dopaminergic antiparkinsonism agents     -   drugs used in alcohol dependence     -   echinocandins     -   EGFR inhibitors     -   estrogen receptor antagonists     -   estrogens     -   expectorants     -   factor Xa inhibitors     -   fatty acid derivative anticonvulsants     -   fibric acid derivatives     -   first generation cephalosporins     -   fourth generation cephalosporins     -   functional bowel disorder agents     -   gallstone solubilizing agents     -   gamma-aminobutyric acid analogs     -   gamma-aminobutyric acid reuptake inhibitors     -   gamma-aminobutyric acid transaminase inhibitors     -   gastrointestinal agents     -   general anesthetics     -   genitourinary tract agents     -   GI stimulants     -   glucocorticoids     -   glucose elevating agents     -   glycopeptide antibiotics     -   glycoprotein platelet inhibitors     -   glycylcyclines     -   gonadotropin releasing hormones     -   gonadotropin-releasing hormone antagonists     -   gonadotropins     -   group I antiarrhythmics     -   group II antiarrhythmics     -   group III antiarrhythmics     -   group IV antiarrhythmics     -   group V antiarrhythmics     -   growth hormone receptor blockers     -   growth hormones     -   H. pylori eradication agents     -   H2 antagonists     -   hematopoietic stem cell mobilizer     -   heparin antagonists     -   heparins     -   HER2 inhibitors     -   herbal products     -   histone deacetylase inhibitors     -   hormone replacement therapy     -   hormones     -   hormones/antineoplastics     -   hydantoin anticonvulsants     -   illicit (street) drugs     -   immune globulins     -   immunologic agents     -   immunosuppressive agents     -   impotence agents     -   in vivo diagnostic biologicals     -   incretin mimetics     -   inhaled anti-infectives     -   inhaled corticosteroids     -   inotropic agents     -   insulin     -   insulin-like growth factor     -   integrase strand transfer inhibitor     -   interferons     -   intravenous nutritional products     -   iodinated contrast media     -   ionic iodinated contrast media     -   iron products     -   ketolides     -   laxatives     -   leprostatics     -   leukotriene modifiers     -   lincomycin derivatives     -   lipoglycopeptides     -   local injectable anesthetics     -   loop diuretics     -   lung surfactants     -   lymphatic staining agents     -   lysosomal enzymes     -   macrolide derivatives     -   macrolides     -   magnetic resonance imaging contrast media     -   mast cell stabilizers     -   medical gas     -   meglitinides     -   metabolic agents     -   methylxanthines     -   mineralocorticoids     -   minerals and electrolytes     -   miscellaneous agents     -   miscellaneous analgesics     -   miscellaneous antibiotics     -   miscellaneous anticonvulsants     -   miscellaneous antidepressants     -   miscellaneous antidiabetic agents     -   miscellaneous antiemetics     -   miscellaneous antifungals     -   miscellaneous antihyperlipidemic agents     -   miscellaneous antimalarials     -   miscellaneous antineoplastics     -   miscellaneous antiparkinson agents     -   miscellaneous antipsychotic agents     -   miscellaneous antituberculosis agents     -   miscellaneous antivirals     -   miscellaneous anxiolytics, sedatives and hypnotics     -   miscellaneous biologicals     -   miscellaneous bone resorption inhibitors     -   miscellaneous cardiovascular agents     -   miscellaneous central nervous system agents     -   miscellaneous coagulation modifiers     -   miscellaneous diuretics     -   miscellaneous genitourinary tract agents     -   miscellaneous GI agents     -   miscellaneous hormones     -   miscellaneous metabolic agents     -   miscellaneous ophthalmic agents     -   miscellaneous otic agents     -   miscellaneous respiratory agents     -   miscellaneous sex hormones     -   miscellaneous topical agents     -   miscellaneous uncategorized agents     -   miscellaneous vaginal agents     -   mitotic inhibitors     -   monoamine oxidase inhibitors     -   monoclonal antibodies     -   mouth and throat products     -   mTOR inhibitors     -   mTOR kinase inhibitors     -   mucolytics     -   multikinase inhibitors     -   muscle relaxants     -   mydriatics     -   narcotic analgesic combinations     -   narcotic analgesics     -   nasal anti-infectives     -   nasal antihistamines and decongestants     -   nasal lubricants and irrigations     -   nasal preparations     -   nasal steroids     -   natural penicillins     -   neuraminidase inhibitors     -   neuromuscular blocking agents     -   next generation cephalosporins     -   nicotinic acid derivatives     -   nitrates     -   NNRTIs     -   non-cardioselective beta blockers     -   non-iodinated contrast media     -   non-ionic iodinated contrast media     -   non-sulfonylureas     -   nonsteroidal anti-inflammatory agents     -   norepinephrine reuptake inhibitors     -   norepinephrine-dopamine reuptake inhibitors     -   nucleoside reverse transcriptase inhibitors (NRT1s)     -   nutraceutical products     -   nutritional products     -   ophthalmic anesthetics     -   ophthalmic anti-infectives     -   ophthalmic anti-inflammatory agents     -   ophthalmic antihistamines and decongestants     -   ophthalmic diagnostic agents     -   ophthalmic glaucoma agents     -   ophthalmic lubricants and irrigations     -   ophthalmic preparations     -   ophthalmic steroids     -   ophthalmic steroids with anti-infectives     -   ophthalmic surgical agents     -   oral nutritional supplements     -   otic anesthetics     -   otic anti-infectives     -   otic preparations     -   otic steroids     -   otic steroids with anti-infectives     -   oxazolidinedione anticonvulsants     -   parathyroid hormone and analogs     -   penicillinase resistant penicillins     -   penicillins     -   peripheral opioid receptor antagonists     -   peripheral vasodilators     -   peripherally acting antiobesity agents     -   phenothiazine antiemetics     -   phenothiazine antipsychotics     -   phenylpiperazine antidepressants     -   plasma expanders     -   platelet aggregation inhibitors     -   platelet-stimulating agents     -   polyenes     -   potassium-sparing diuretics     -   probiotics     -   progesterone receptor modulators     -   progestins     -   prolactin inhibitors     -   prostaglandin D2 antagonists     -   protease inhibitors     -   proton pump inhibitors     -   psoralens     -   psychotherapeutic agents     -   psychotherapeutic combinations     -   purine nucleosides     -   pyrrolidine anticonvulsants     -   quinolones     -   radiocontrast agents     -   radiologic adjuncts     -   radiologic agents     -   radiologic conjugating agents     -   radiopharmaceuticals     -   RANK ligand inhibitors     -   recombinant human erythropoietins     -   renin inhibitors     -   respiratory agents     -   respiratory inhalant products     -   rifamycin derivatives     -   salicylates     -   sclerosing agents     -   second generation cephalosporins     -   selective estrogen receptor modulators     -   selective serotonin reuptake inhibitors     -   serotonin-norepinephrine reuptake inhibitors     -   serotoninergic neuroenteric modulators     -   sex hormone combinations     -   sex hormones     -   skeletal muscle relaxant combinations     -   skeletal muscle relaxants     -   smoking cessation agents     -   somatostatin and somatostatin analogs     -   spermicides     -   statins     -   sterile irrigating solutions     -   streptomyces derivatives     -   succinimide anticonvulsants     -   sulfonamides     -   sulfonylureas     -   synthetic ovulation stimulants     -   tetracyclic antidepressants     -   tetracyclines     -   therapeutic radiopharmaceuticals     -   thiazide diuretics     -   thiazolidinediones     -   thioxanthenes     -   third generation cephalosporins     -   thrombin inhibitors     -   thrombolytics     -   thyroid drugs     -   tocolytic agents     -   topical acne agents     -   topical agents     -   topical anesthetics     -   topical anti-infectives     -   topical antibiotics     -   topical antifungals     -   topical antihistamines     -   topical antipsoriatics     -   topical antivirals     -   topical astringents     -   topical debriding agents     -   topical depigmenting agents     -   topical emollients     -   topical keratolytics     -   topical steroids     -   topical steroids with anti-infectives     -   toxoids     -   triazine anticonvulsants     -   tricyclic antidepressants     -   trifunctional monoclonal antibodies     -   tumor necrosis factor (TNF) inhibitors     -   tyrosine kinase inhibitors     -   ultrasound contrast media     -   upper respiratory combinations     -   urea anticonvulsants     -   urinary anti-infectives     -   urinary antispasmodics     -   urinary pH modifiers     -   uterotonic agents     -   vaccine     -   vaccine combinations     -   vaginal anti-infectives     -   vaginal preparations     -   vasodilators     -   vasopressin antagonists     -   vasopressors     -   VEGF/VEGFR inhibitors     -   viral vaccines     -   viscosupplementation agents     -   vitamin and mineral combinations     -   vitamins

Diagnostic Tests

-   -   17-Hydroxyprogesterone     -   ACE (Angiotensin I converting enzyme)     -   Acetaminophen     -   Acid phosphatase     -   ACTH     -   Activated clotting time     -   Activated protein C resistance     -   Adrenocorticotropic hormone (ACTH)     -   Alanine aminotransferase (ALT)     -   Albumin     -   Aldolase     -   Aldosterone     -   Alkaline phosphatase     -   Alkaline phosphatase (ALP)     -   Alpha1-antitrypsin     -   Alpha-fetoprotein     -   Alpha-fetoprotien     -   Ammonia levels     -   Amylase     -   ANA (antinuclear antbodies)     -   ANA (antinuclear antibodies)     -   Angiotensin-converting enzyme (ACE)     -   Anion gap     -   Anticardiolipin antibody     -   Anticardiolipin antivbodies (ACA)     -   Anti-centromere antibody     -   Antidiuretic hormone     -   Anti-DNA     -   Anti-Dnase-B     -   Anti-Gliadin antibody     -   Anti-glomerular basement membrane antibody     -   Anti-HBc (Hepatitis B core antibodies     -   Anti-HBs (Hepatitis B surface antibody     -   Antiphospholipid antibody     -   Anti-RNA polymerase     -   Anti-Smith (Sm) antibodies     -   Anti-Smooth Muscle antibody     -   Antistreptolysin O (ASO)     -   Antithrombin III     -   Anti-Xa activity     -   Anti-Xa assay     -   Apolipoproteins     -   Arsenic     -   Aspartate aminotransferase (AST)     -   B12     -   Basophil     -   Beta-2-Microglobulin     -   Beta-hydroxybutyrate     -   B-HCG     -   Bilirubin     -   Bilirubin, direct     -   Bilirubin, indirect     -   Bilirubin, total     -   Bleeding time     -   Blood gases (arterial)     -   Blood urea nitrogen (BUN)     -   BUN     -   BUN (blood urea nitrogen)     -   CA 125     -   CA 15-3     -   CA 19-9     -   Calcitonin     -   Calcium     -   Calcium (ionized)     -   Carbon monoxide (CO)     -   Carcinoembryonic antigen (CEA)     -   CBC     -   CEA     -   CEA (carcinoembryonic antigen)     -   Ceruloplasmin     -   CH50Chloride     -   Cholesterol     -   Cholesterol, HDL     -   Clot lysis time     -   Clot retraction time     -   CMP     -   CO₂     -   Cold agglutinins     -   Complement C3     -   Copper     -   Corticotrophin releasing hormone (CRH) stimulation test     -   Cortisol     -   Cortrosyn stimulation test     -   C-peptide     -   CPK (Total)     -   CPK-MB     -   C-reactive protein     -   Creatinine     -   Creatinine kinase (CK)     -   Cryoglobulins     -   DAT (Direct antiglobulin test)     -   D-Dimer     -   Dexamethasone suppression test     -   DHEA-S     -   Dilute Russell viper venom     -   Elliptocytes     -   Eosinophil     -   Erythrocyte sedimentation rate (ESR)     -   Estradiol     -   Estriol     -   Ethanol     -   Ethylene glycol     -   Euglobulin lysis     -   Factor V Leiden     -   Factor VIII inhibitor     -   Factor VIII level     -   Ferritin     -   Fibrin split products     -   Fibrinogen     -   Folate     -   Folate (serum     -   Fractional excretion of sodium (FENA)     -   FSH (follicle stimulating factor)     -   FTA-ABS     -   Gamma glutamyl transferase (GGT)     -   Gastrin     -   GGTP (Gamma glutamyl transferase)     -   Glucose     -   Growth hormone     -   Haptoglobin     -   HBeAg (Hepatitis Be antigen)     -   HBs-Ag (Hepatitis B surface antigen)     -   Helicobacter pylori     -   Hematocrit     -   Hematocrit (HCT)     -   Hemoglobin     -   Hemoglobin A1C     -   Hemoglobin electrophoresis     -   Hepatitis A antibodies     -   Hepatitis C antibodies     -   IAT (Indirect antiglobulin test)     -   Immunofixation (IFE)     -   Iron     -   Lactate dehydrogenase (LDH)     -   Lactic acid (lactate)     -   LDH     -   LH (Leutinizing hormone     -   Lipase     -   Lupus anticoagulant     -   Lymphocyte     -   Magnesium     -   MCH (mean corpuscular hemoglobin     -   MCHC (mean corpuscular hemoglobin concentration)     -   MCV (mean corpuscular volume)     -   Methylmalonate     -   Monocyte     -   MPV (mean platelet volume)     -   Myoglobin     -   Neutrophil     -   Parathyroid hormone (PTH)     -   Phosphorus     -   Platelets (plt)     -   Potassium     -   Prealbumin     -   Prolactin     -   Prostate specific antigen (PSA)     -   Protein C     -   Protein S     -   PSA (prostate specific antigen)     -   PT (Prothrombin time)     -   PTT (Partial thromboplastin time)     -   RDW (red cell distribution width)     -   Renin     -   Rennin     -   Reticulocyte count     -   reticulocytes     -   Rheumatoid factor (RF)     -   Sed Rate     -   Serum glutamic-pyruvic transaminase (SGPT     -   Serum protein electrophoresis (SPEP)     -   Sodium     -   T3-resin uptake (T3RU)     -   T4, Free     -   Thrombin time     -   Thyroid stimulating hormone (TSH)     -   Thyroxine (T4     -   Total iron binding capacity (TIBC)     -   Total protein     -   Transferrin     -   Transferrin saturation     -   Triglyceride (TG)     -   Troponin     -   Uric acid     -   Vitamin B12     -   White blood cells (WBC)     -   Widal test

As several examples, the fluid material 40 can be an inhalation anesthetic, a drug, or a diagnostic test material. Any of these fluid materials 40 can be an injectable material, a volatile material capable of being inhaled, or otherwise capable of being introduced into a subject.

Other Uses of the Passivation Layer or pH Protective Coating

A vessel with a passivation layer or pH protective coating as described herein can also be evacuated and stored in an evacuated state. For example, the passivation layer or pH protective coating allows better maintenance of the vacuum in comparison to a corresponding vessel without a passivation layer or pH protective coating. In one aspect of this embodiment, the vessel with a passivation layer or pH protective coating can be a blood collection tube. The tube can also contain an agent for preventing blood clotting or platelet activation, for example EDTA or heparin.

Even another embodiment can be a medical or diagnostic kit including a vessel having a passivation layer or pH protective coating as defined in any embodiment herein on a substrate as defined in any embodiment herein. Optionally, the kit additionally includes a medicament or diagnostic agent as defined in any embodiment herein which is contained in the vessel with a passivation layer or pH protective coating in contact with the coating or layer; and/or a hypodermic needle, double-ended needle, or other delivery conduit; and/or an instruction sheet.

Use of the passivation layer or pH protective coating according to any described embodiment is contemplated for preventing or reducing precipitation and/or clotting or platelet activation of a compound or a component of the composition in contact with the coating or layer.

The use of a coated substrate according to any described embodiment is contemplated for storing insulin. As one option, precipitation of the insulin can be prevented or reduced by providing vessel to contain the insulin having a contact surface including a passivation layer or pH protective coating.

As another option, the compound or a component of the composition can be blood or a blood fraction, and blood clotting or platelet activation can be prevented or reduced by storing the blood in the blood collection tube in contact with a passivation layer or pH protective coating. Optionally, the blood collection tube can contain an agent for preventing blood clotting or platelet activation, for example ethylenediamineteetraacetic acid (EDTA), a sodium salt thereof, or heparin. The blood collection tube can include a passivation layer or pH protective coating for preventing the agent from attacking an SiO_(x) barrier coating or layer in the vessel. The use of a coated substrate according to any described embodiment is contemplated for storing blood. Optionally, the stored blood can be viable for return to the vascular system of a patient.

Use of a coating or layer according to any described embodiment can be contemplated as (i) a lubricity coating having a lower frictional resistance than the uncoated surface; and/or (ii) a passivation layer or pH protective coating preventing dissolution of the barrier coating or layer in contact with a fluid, and/or (iii) a hydrophobic layer that can be more hydrophobic than the uncoated surface.

Measurement of Coating Thickness

The thickness of a PECVD coating or layer such as the passivation layer or pH protective coating, the barrier coating or layer, the lubricity coating or layer, and/or a composite of any two or more of these layers can be measured, for example, by transmission electron microscopy (TEM).

The TEM can be carried out, for example, as follows. Samples can be prepared for Focused Ion Beam (FIB) cross-sectioning in two ways. Either the samples can be first coated with a thin layer of carbon (50-100 nm thick) and then coated with a sputtered coating or layer of platinum (50-100 nm thick) using a K575X Emitech passivation layer or pH protective coating system, or the samples can be coated directly with the protective sputtered Pt layer. The coated samples can be placed in an FEI FIB200 FIB system. An additional coating or layer of platinum can be FIB-deposited by injection of an organometallic gas while rastering the 30 kV gallium ion beam over the area of interest. The area of interest for each sample can be chosen to be a location half way down the length of the syringe barrel. Thin cross sections measuring approximately 15 μm (“micrometers”) long, 2 μm wide and 15 μm deep can be extracted from the die surface using an in-situ FIB lift-out technique. The cross sections can be attached to a 200 mesh copper TEM grid using FIB-deposited platinum. One or two windows in each section, measuring about 8 μm wide, can be thinned to electron transparency using the gallium ion beam of the FEI FIB.

Cross-sectional image analysis of the prepared samples can be performed utilizing either a Transmission Electron Microscope (TEM), or a Scanning Transmission Electron Microscope (STEM), or both. All imaging data can be recorded digitally. For STEM imaging, the grid with the thinned foils can be transferred to a Hitachi HD2300 dedicated STEM. Scanning transmitted electron images can be acquired at appropriate magnifications in atomic number contrast mode (ZC) and transmitted electron mode (TE). The following instrument settings can be used.

Scanning Transmission Instrument Electron Microscope Manufacturer/Model Hitachi HD2300 Accelerating Voltage 200 kV Objective Aperture #2 Condenser Lens 1 Setting 1.672 Condenser Lens 2 Setting 1.747 Approximate Objective Lens 5.86 Setting ZC Mode Projector Lens 1.149 TE Mode Projector Lens 0.7 Image Acquisition 1280 × 960 Pixel Resolution Acquisition Time 20 sec. (×4

For TEM analysis the sample grids can be transferred to a Hitachi HF2000 transmission electron microscope. Transmitted electron images can be acquired at appropriate magnifications. The relevant instrument settings used during image acquisition can be those given below.

Instrument Transmission Electron Microscope Manufacturer/Model Hitachi HF2000 Accelerating Voltage 200 kV Condenser Lens 1 0.78 Condenser Lens 2 0 Objective Lens 6.34 Condenser Lens #1 Aperture Objective Lens Aperture #3 for imaging Selective Area Aperture N/A for SAD

Basic Protocols for Forming and Coating Syringe Barrels

The pharmaceutical packages or other vessels tested in the subsequent working examples were formed and coated according to the following exemplary protocols, except as otherwise indicated in individual examples. Particular parameter values given in the following basic protocols, for example the electric power and gaseous reactant or process gas flow, are typical values. When parameter values were changed in comparison to these typical values, this will be indicated in the subsequent working examples. The same applies to the type and composition of the gaseous reactant or process gas.

In some instances, the reference characters and Figures mentioned in the following protocols and additional details can be found in U.S. Pat. No. 7,985,188.

Protocol for Coating Syringe Barrel Interior with SiO_(x)

The apparatus and protocol generally as found in U.S. Pat. No. 7,985,188 were used for coating syringe barrel interiors with an SiO_(x) barrier coating or layer, in some cases with minor variations. A similar apparatus and protocol were used for coating vials with an SiO_(x) barrier coating or layer, in some cases with minor variations.

Protocol for Coating Syringe Barrel Interior with OMCTS Passivation Layer or pH Protective Coating

Syringe barrels already interior coated with a barrier coating or layer of SiO_(x), as previously identified, are further interior coated with a passivation layer or pH protective coating as previously identified, generally following the protocols of U.S. Pat. No. 7,985,188 for applying the lubricity coating or layer, except with modified conditions in certain instances as noted in the working examples. The conditions given here are for a COC syringe barrel, and can be modified as appropriate for syringe barrels made of other materials. The apparatus as generally shown in FIG. 4 can be used to hold a syringe barrel with butt sealing at the base of the syringe barrel.

The syringe barrel is carefully moved into the sealing position over the extended probe or counter electrode 108 and pushed against a plasma screen. The plasma screen is fit snugly around the probe or counter electrode 108 insuring good electrical contact. The probe or counter electrode 108 is grounded to the casing of the RF matching network.

The gas delivery port 110 is connected to a manual ball valve or similar apparatus for venting, a thermocouple pressure gauge and a bypass valve connected to the vacuum pumping line. In addition, the gas system is connected to the gas delivery port 110 allowing the gaseous reactant or process gas, octamethylcyclotetrasiloxane (OMCTS) (or the specific gaseous reactant or process gas reported for a particular example) to be flowed through the gas delivery port 110 (under process pressures) into the interior of the syringe barrel.

The gas system is comprised of a commercially available heated mass flow vaporization system that heats the OMCTS to about 100° C. The heated mass flow vaporization system is connected to liquid octamethylcyclotetrasiloxane (Alfa Aesar® Part Number A12540, 98%). The OMCTS flow rate is set to the specific organosilicon precursor flow reported for a particular example. To ensure no condensation of the vaporized OMCTS flow past this point, the gas stream is diverted to the pumping line when it is not flowing into the interior of the COC syringe barrel for processing.

Once the syringe barrel is installed, the vacuum pump valve is opened to the vessel support 50 and the interior of the COC syringe barrel. A vacuum pump and blower comprise the vacuum pump system. The pumping system allows the interior of the COC syringe barrel to be reduced to pressure(s) of less than 100 mTorr while the gaseous reactant or process gases is flowing at the indicated rates.

Once the base vacuum level is achieved, the vessel support 50 assembly is moved into the electrode 160 assembly. The gas stream (OMCTS vapor) is flowed into the gas delivery port 110 (by adjusting the 3-way valve from the pumping line to the gas delivery port 110. The plasma for PECVD, if used, can be generated at reduced pressure and the reduced pressure can be less than 300 mTorr, optionally less than 200 mTorr, even optionally less than 100 mTorr. Pressure inside the COC syringe barrel can be, as one example, approximately 140 mTorr as measured by a capacitance manometer (MKS) installed on the pumping line near the valve that controls the vacuum. In addition to the COC syringe barrel pressure, the pressure inside the gas delivery port 110 and gas system is also measured with the thermocouple vacuum gauge that is connected to the gas system. This pressure is typically less than 6 Torr.

Once the gas is flowing to the interior of the COC syringe barrel, the RF power supply is turned on to its fixed power level or as otherwise indicated in a specific example or description. The physical and chemical properties of the passivation layer or pH protective coating can be set by setting the ratio of oxidizing gas to the organosilicon precursor in the gaseous reactant, and/or by setting the electric power used for generating the plasma. A 600 Watt RF power supply is used (at 13.56 MHz) at a fixed power level or as otherwise indicated in a specific example or description. The RF power supply is connected to an auto match which matches the complex impedance of the plasma (to be created in the vessel) to the output impedance of the RF power supply. The forward power is as stated and the reflected power is 0 Watts so that the stated power is delivered to the interior of the vessel. The RF power supply is controlled by a laboratory timer and the power on time set to 10 seconds (or a different time stated in a given example).

Upon initiation of the RF power, uniform plasma is established inside the interior of the vessel. The plasma is maintained for the entire passivation layer or pH protective coating time, until the RF power is terminated by the timer. The plasma produces a passivation layer or pH protective coating on the interior of the vessel.

After applying the passivation layer or pH protective coating, the gas flow is diverted back to the vacuum line and the vacuum valve is closed. The vent valve is then opened, returning the interior of the COC syringe barrel to atmospheric pressure (approximately 760 Torr). The treated vessel is then carefully removed from the vessel support 50 assembly (after moving the vessel support 50 assembly out of the electrode 160 assembly).

A similar protocol is used, except using apparatus generally like that of FIG. 1, for applying a passivation layer or pH protective coating to vials.

Protocol for Total Silicon Measurement

This protocol is used to determine the total amount of silicon coatings present on the entire vessel wall. A supply of 0.1 N potassium hydroxide (KOH) aqueous solution is prepared, taking care to avoid contact between the solution or ingredients and glass. The water used is purified water, 18 KΩ quality. A Perkin Elmer Optima Model 7300DV ICP-OES instrument is used for the measurement except as otherwise indicated.

Each device (vial, syringe, tube, or the like) to be tested and its cap and crimp (in the case of a vial) or other closure are weighed empty to 0.001 g, then filled completely with the KOH solution (with no headspace), capped, crimped, and reweighed to 0.001 g. In a digestion step, each vial is placed in a sonicating water bath at 40° C. for a minimum of 8-10 hours. The digestion step is carried out to quantitatively remove the silicon coatings from the vessel wall into the KOH solution. After this digestion step, the vials are removed from the sonicating water bath and allowed to cool to room temperature. The contents of the vials are transferred into 15 ml ICP tubes. The total Si concentration is run on each solution by ICP/OES following the operating procedure for the ICP/OES.

The total Si concentration is reported as parts per billion of Si in the KOH solution. This concentration represents the total amount of silicon coatings that were on the vessel wall before the digestion step was used to remove it.

The total Si concentration can also be determined for fewer than all the silicon layers on the vessel, as when an SiO_(x) barrier coating or layer is applied, an SiO_(x)C_(y) second layer (for example, a lubricity layer or a passivation layer or pH protective coating) is then applied, and it is desired to know the total silicon concentration of just the SiO_(x)C_(y) layer. This determination is made by preparing two sets of vessels, one set to which only the SiO_(x) layer is applied and the other set to which the same SiO_(x) layer is applied, followed by the SiO_(x)C_(y) layer or other layers of interest. The total Si concentration for each set of vessels is determined in the same manner as described above. The difference between the two Si concentrations is the total Si concentration of the SiO_(x)C_(y) second layer.

Protocol for Measuring Dissolved Silicon in a Vessel

In some of the working examples, the amount of silicon dissolved from the wall of the vessel by a test solution is determined, in parts per billion (ppb), for example to evaluate the dissolution rate of the test solution. This determination of dissolved silicon is made by storing the test solution in a vessel provided with an SiO_(x) and/or SiO_(x)C_(y) coating or layer under test conditions, then removing a sample of the solution from the vessel and testing the Si concentration of the sample. The test is done in the same manner as the Protocol for Total Silicon Measurement, except that the digestion step of that protocol is replaced by storage of the test solution in the vessel as described in this protocol. The total Si concentration is reported as parts per billion of Si in the test solution

Protocol for Determining Average Dissolution Rate

The average dissolution rates reported in the working examples are determined as follows. A series of test vessels having a known total silicon measurement are filled with the desired test solution analogous to the manner of filling the vials with the KOH solution in the Protocol for Total Silicon Measurement. (The test solution can be a physiologically inactive test solution as employed in the present working examples or a physiologically active pharmaceutical preparation intended to be stored in the vessels to form a pharmaceutical package). The test solution is stored in respective vessels for several different amounts of time, then analyzed for the Si concentration in parts per billion in the test solution for each storage time. The respective storage times and Si concentrations are then plotted. The plots are studied to find a series of substantially linear points having the steepest slope.

The plot of dissolution amount (ppb Si) versus days decreases in slope with time. It is believed that the dissolution rate is not flattening out because the Si layer has been fully digested by the test solution.

For the PC₁₉₄ test data in Table 10 below, linear plots of dissolution versus time data are prepared by using a least squares linear regression program to find a linear plot corresponding to the first five data points of each of the experimental plots. The slope of each linear plot is then determined and reported as representing the average dissolution rate applicable to the test, measured in parts per billion of Si dissolved in the test solution per unit of time.

Protocol for Determining Calculated Shelf Life

The calculated shelf life values reported in the working examples below are determined by extrapolation of the total silicon measurements and average dissolution rates, respectively determined as described in the Protocol for Total Silicon Measurement and the Protocol for Determining Average Dissolution Rate. The assumption is made that under the indicated storage conditions the SiO_(x)C_(y) passivation layer or pH protective coating will be removed at the average dissolution rate until the coating is entirely removed. Thus, the total silicon measurement for the vessel, divided by the dissolution rate, gives the period of time required for the test solution to totally dissolve the SiO_(x)C_(y) coating. This period of time is reported as the calculated shelf life. Unlike commercial shelf life calculations, no safety factor is calculated. Instead, the calculated shelf life is the calculated time to failure.

It should be understood that because the plot of ppb Si versus hours decreases in slope with time, an extrapolation from relatively short measurement times to relatively long calculated shelf lives is believed to be a “worst case” test that tends to underestimate the calculated shelf life actually obtainable.

SEM Procedure

SEM Sample Preparation: Each syringe sample was cut in half along its length (to expose the inner or interior surface). The top of the syringe (Luer end) was cut off to make the sample smaller.

The sample was mounted onto the sample support with conductive graphite adhesive, then put into a Denton Desk IV SEM Sample Preparation System, and a thin (approximately 50 Å) gold passivation layer or pH protective coating was sputtered onto the inner or interior surface of the syringe. The gold passivation layer or pH protective coating is required to eliminate charging of the surface during measurement.

The sample was removed from the sputter system and mounted onto the sample stage of a Jeol JSM 6390 SEM (Scanning Electron Microscope). The sample was pumped down to at least 1×10-6 Torr in the sample compartment. Once the sample reached the required vacuum level, the slit valve was opened and the sample was moved into the analysis station.

The sample was imaged at a coarse resolution first, then higher magnification images were accumulated. The SEM images provided in the Figures are 5 μm edge-to-edge (horizontal and vertical).

AFM (Atomic Force Microscopy) Procedure.

AFM images were collected using a NanoScope III Dimension 3000 machine (Digital Instruments, Santa Barbara, Calif., USA). The instrument was calibrated against a NIST traceable standard. Etched silicon scanning probe microscopy (SPM) tips were used. Image processing procedures involving auto-flattening, plane fitting or convolution were employed. One 10 μm×10 μm area was imaged. Roughness analyses were performed and were expressed in: (1) Root-Mean-Square Roughness, RMS; 2 Mean Roughness, Ra; and (3) Maximum Height (Peak-to-Valley), Rmax, all measured in nm (see Table 5). For the roughness analyses, each sample was imaged over the 10 μm×10 μm area, followed by three cross sections selected by the analyst to cut through features in the 10 μm×10 μm images. The vertical depth of the features was measures using the cross section tool. For each cross section, a Root-Mean-Square Roughness (RMS) in nanometers was reported. These RMS values along with the average of the three cross sections for each sample are listed in Table 5.

Additional analysis of the 10 μm×10 μm images represented by Examples Q, T and V was carried out. For this analysis three cross sections were extracted from each image. The locations of the cross sections were selected by the analyst to cut through features in the images. The vertical depth of the features was measured using the cross section tool.

The Digital Instruments Nanoscope III AFM/STM acquires and stores 3-dimensional representations of surfaces in a digital format. These surfaces can be analyzed in a variety of ways.

The Nanoscope III software can perform a roughness analysis of any AFM or STM image. The product of this analysis is a single page reproducing the selected image in top view. To the upper right of the image is the “Image Statistics” box, which lists the calculated characteristics of the whole image minus any areas excluded by a stopband (a box with an X through it). Similar additional statistics can be calculated for a selected portion of the image and these are listed in the “Box Statistics” in the lower right portion of the page. What follows is a description and explanation of these statistics.

Image Statistics:

Z Range (Rp): The difference between the highest and lowest points in the image. The value is not corrected for tilt in the plane of the image; therefore, plane fitting or flattening the data will change the value.

Mean: The average of all of the Z values in the imaged area. This value is not corrected for the tilt in the plane of the image; therefore, plane fitting or flattening the data will change this value.

RMS (Rq): This is the standard deviation of the Z values (or RMS roughness) in the image. It is calculated according to the formula:

Rq={Σ(Z1−Zavg)2/N}

where Zavg is the average Z value within the image; Z1 is the current value of Z; and N is the number of points in the image. This value is not corrected for tilt in the plane of the image; therefore, plane fitting or flattening the data will change this value.

Mean roughness (Ra): This is the mean value of the surface relative to the Center Plane and is calculated using the formula:

Ra=[1/(LxLy)]∫oLy∫oLx{f(x,y)}dxdy

where f(x,y) is the surface relative to the Center plane, and Lx and Ly are the dimensions of the surface.

Max height (Rmax): This is the difference in height between the highest and lowest points of the surface relative to the Mean Plane.

Surface area: (Optical calculation): This is the area of the 3-dimensional surface of the imaged area. It is calculated by taking the sum of the areas of the triangles formed by 3 adjacent data points throughout the image.

Surface area diff: (Optional calculation) This is the amount that the Surface area is in excess of the imaged area. It is expressed as a percentage and is calculated according to the formula:

Surface area diff=100[(Surface area/S12−1]

where S1 is the length (and width) of the scanned area minus any areas excluded by stopbands.

Center Plane: A flat plane that is parallel to the Mean Plane. The volumes enclosed by the image surface above and below the center plane are equal.

Mean Plane: The image data has a minimum variance about this flat plane. It results from a first order least squares fit on the Z data.

WORKING EXAMPLES Comparative Example 1 Thickness Profile for pH-Protective Coating or Layer

A pH protective coating (e.g. 34) was applied to the surface (16) of the wall of a syringe. The gas inlet used was provided with the 90-degree perforation pattern shown in FIG. 26. The external electrode was a solid metallic tube. The protocol provided above was generally followed, using 30 Watts of RF energy, OMCTS as a precursor at a flow rate of 2 sccm, argon as a diluent at a flow rate of 20 sccm, oxygen gas as an oxidizing gas at a flow rate of 0.5 sccm, and a continuous plasma energization time of 10 sec. No magnets were used in this example.

The shelf life or rate of dissolution of the pH protective coating in 0.1 M KOH was measured, and found to be 127 days for the complete coating. A plot of the coating thickness as a function of the position on a cylindrical portion of the syringe barrel is provided as FIG. 30. The plot shows a region of very thick deposition at about 50 degrees around the circumference of the syringe, regions of very little deposition thickness as measured at about 220 to 300 degrees, and gradations of deposition up the full height of the syringe surface between 270 and 800 degrees. The statistical data captured during this test is as follows:

Quantiles 100.00%  maximum 1279 99.5% 1279 97.5% 1187.3 90.0% 849.44 75.0% Quartile 547.35 50.0% Median 329.3 25.0% Quartile 158.95 10.0% 25.088  2.5% 0.5  .5% 0.5  0.0% Minimum 0.5 Moments Mean 384.7021 Std Dev. 306.1763 Std Err Mean 34.019589 Upper 95% Mean 452.40324 Lower 95% Mean 317.00096 N 81

The above tables show that the standard deviation of thickness was 306 nm, the mean thickness was 385 nm, and the ratio of (one) standard deviation to the mean thickness was 0.79. This high standard deviation and high ratio is indicative of a non-uniform coating, relative to the examples according to the present invention.

Example 2 Thickness Profile for pH-Protective Coating or Layer

A pH protective coating (e.g. 34) was applied to the surface (16) of the wall of a syringe. The gas inlet used was provided with the 120-degree or triangular perforation pattern shown in FIG. 27. The protocol provided above was generally followed, using 20 Watts of RF energy, OMCTS as a precursor at a flow rate of 2 sccm, argon as a diluent at a flow rate of 20 sccm, oxygen gas as an oxidizing gas at a flow rate of 0.5 sccm, and a continuous plasma energization time of 5 sec. A stationary quadrupole magnet array using ceramic magnets, generally as shown in FIGS. 4-5, was used, as was a wire mesh electrode.

The shelf life or rate of dissolution of the pH protective coating in 0.1 M KOH was measured. The coating did not dissolve in standard 0.1 M KOH. A plot of the coating thickness as a function of the position on a cylindrical portion of the syringe barrel is provided as FIG. 31. The plot shows more uniform deposition of the coating and a coating desirably more resistant to dissolution, with isolated regions of thicker deposition at about 80, 200, and 320 degrees around the circumference of the syringe and 15, 25, and 40 mm along the height of the syringe surface. These discontinuities are believed to result from the perforation pattern in the gas inlet. The statistical data captured during this test is as follows:

Quantiles 100.00%  maximum 1070 99.5% 1070 97.5% 855.63 90.0% 533.02 75.0% Quartile 437.35 50.0% Median 359.4 25.0% Quartile 276.25 10.0% 195.8  2.5% 90.7975  .5% 45.47  0.0% Minimum 45.47 Moments Mean 369.0484 Std Dev. 161.4856 Std Err Mean 17.942845 Upper 95% Mean 404.75579 Lower 95% Mean 333.341 N 81

The above tables show that the standard deviation of thickness was 161 nm, the mean thickness was 369 nm (similar to Example 1), and the ratio of (one) standard deviation to the mean thickness was 0.44. This much lower standard deviation and ratio is indicative of a much more uniform coating, relative to Example 1.

Example 3 Thickness Profile for pH-Protective Coating or Layer

A pH protective coating (e.g. 34) was applied to the surface (16) of the wall of a syringe. The gas inlet used was provided with the 45-degree or spiral perforation pattern shown in FIG. 28. The protocol provided above was generally followed, using 20 Watts of RF energy, OMCTS as a precursor at a flow rate of 2 sccm, argon as a diluent at a flow rate of 20 sccm, oxygen gas as an oxidizing gas at a flow rate of 0.5 sccm, and a continuous plasma energization time of 10 sec. A stationary quadrupole magnet array using neodymium-iron-boron (NDFeB or neodymium) magnets, generally as shown in FIGS. 4-5, was used, as was a wire mesh electrode.

A plot of the coating thickness as a function of the position on a cylindrical portion of the syringe barrel is provided as FIG. 32. The plot shows more uniform deposition of the coating, with isolated regions of thicker deposition across the height at about 0 and 180 degrees around the circumference of the syringe. While the reason for this variation in thickness is not known, comparison with Example 4 suggests that this variation may be the result of different deposition thickness in a region confronting a north pole versus a south pole of the quadrupole array. The statistical data captured during this test is as follows:

Quantiles 100.00%  maximum 1077 99.5% 1077 97.5% 1018.51 90.0% 839.7 75.0% Quartile 748.4 50.0% Median 555.7 25.0% Quartile 380.95 10.0% 211.8  2.5% 177.64  .5% 109.3  0.0% Minimum 109.3 Moments Mean 588.68025 Std Dev. 233.19587 Std Err Mean 25.910652 Upper 95% Mean 610.24409 Lower 95% Mean 507.11641 N 81

The above tables show that the standard deviation of thickness was 233 nm, the mean thickness was much thicker than previous examples, at 559 nm, and the ratio of (one) standard deviation to the mean thickness was 0.42. This standard deviation ratio was similar to Example 2.

Example 4 Thickness Profile for pH-Protective Coating or Layer

A pH protective coating (e.g. 34) was applied to the surface (16) of the wall of a syringe. The gas inlet used was provided with the 45-degree or spiral perforation pattern shown in FIG. 28. The protocol provided above was generally followed, using 20 Watts of RF energy, OMCTS as a precursor at a flow rate of 2 sccm, argon as a diluent at a flow rate of 20 sccm, oxygen gas as an oxidizing gas at a flow rate of 0.5 sccm, and a continuous plasma energization time of 10 sec. The same quadrupole magnet array and wire mesh electrode of Example 3 was used, except that the quadrupole magnet array was rotated about its axis during deposition.

A plot of the coating thickness as a function of the position on a cylindrical portion of the syringe barrel is provided as FIG. 33. The plot shows still more uniform deposition of the coating than previous examples, with less variation of deposition thickness around the circumference and relatively little difference in deposition thickness across the height. The statistical data captured during this test is as follows:

Quantiles 100.00%  maximum 510 99.5% 510 97.5% 507.13 90.0% 477.18 75.0% Quartile 429.75 50.0% Median 365.8 25.0% Quartile 299.2 10.0% 259.76  2.5% 233.045  .5% 229.8  0.0% Minimum 229.8 Moments Mean 367.92963 Std Dev. 78.695841 Std Err Mean 8.7439823 Upper 95% Mean 385.33071 Lower 95% Mean 350.52855 N 81

The above tables show that the standard deviation of thickness was 79 nm, the mean thickness was 367 nm, and the ratio of (one) standard deviation to the mean thickness was 0.22. This standard deviation ratio was much smaller, showing a much more uniform coating, than Examples 1-3.

Example 5 Thickness Profile for pH-Protective Coating or Layer

A pH protective coating (e.g. 34) was applied to the surface (16) of the wall of a syringe. The gas inlet used was provided with the 45-degree or spiral perforation pattern shown in FIG. 28. The protocol provided above was generally followed, using 20 Watts of RF energy, OMCTS as a precursor at a flow rate of 2 sccm, argon as a diluent at a flow rate of 20 sccm, oxygen gas as an oxidizing gas at a flow rate of 0.5 sccm, and a continuous plasma energization time of 10 sec. A stack of two multi-pole NdFeB ring magnets was used as the magnet array and a solid tubular electrode was used. The magnet array was stationary during deposition.

A plot of the coating thickness as a function of the position on a cylindrical portion of the syringe barrel is provided as FIG. 34. The plot shows still more uniform deposition of the coating than previous example1, though not as uniform as Examples 2-4. The statistical data captured during this test is as follows:

Quantiles 100.00%  maximum 573.3 99.5% 573.3 97.5% 571.42 90.0% 409.1 75.0% Quartile 231.35 50.0% Median 152.3 25.0% Quartile 133.8 10.0% 113.22  2.5% 20.2345  .5% 7.37  0.0% Minimum 7.37 Moments Mean 200.46383 Std Dev. 121.7286 Std Err Mean 13.5254 Upper 95% Mean 227.38023 Lower 95% Mean 173.54742 N 81

The above tables show that the standard deviation of thickness was 122 nm, the mean thickness was 200 nm, and the ratio of (one) standard deviation to the mean thickness was 0.61. The results appear to be skewed by a spot of zero measured deposition at minimal height and an angle of 0 to 50 degrees.

Example 6 Thickness Profile for Barrier Coating or Layer

A SiO_(x) barrier coating or layer (e.g. 30) was applied to the surface (16) of the wall of a syringe. The gas inlet used was provided with the 45-degree or spiral perforation pattern shown in FIG. 28. The barrier layer coating protocol provided above was generally followed, using 35 Watts of RF energy, HMDSO as a precursor at a flow rate of 10 sccm, nodiluents, oxygen gas as an oxidizing gas at a flow rate of 25 sccm, and a continuous plasma energization time of 10 sec, applied three times (total energization time 30 sec). The NdFeB quadrupole of previous examples was used as the magnet array and a mesh electrode was used. The magnet array was stationary during deposition.

A plot of the coating thickness as a function of the position on a cylindrical portion of the syringe barrel is provided as FIG. 35. The plot shows still more uniform deposition of the coating than previous example 1. The statistical data captured during this test is as follows:

Quantiles 100.00%  maximum 631.1 99.5% 631.1 97.5% 546.955 90.0% 417.6 75.0% Quartile 375.2 50.0% Median 301.6 25.0% Quartile 246.5 10.0% 111.44  2.5% 23.7965  .5% 14.92  0.0% Minimum 14.92 Moments Mean 296.8616 Std Dev. 122.54112 Std Err Mean 13.61568 Upper 95% Mean 323.95767 Lower 95% Mean 236.76554 N 81

The above tables show that the standard deviation of thickness was 123 nm, the mean thickness was 297 nm, and the ratio of (one) standard deviation to the mean thickness was 0.41. The barrier improvement factor of the coating was found to be 4.5, indicating value of the coating as a barrier layer. 

1. A method of plasma modifying a vessel having a surface to be treated, the method comprising: providing plasma in or near the surface under conditions effective for plasma modification of the surface of the vessel; and at least part of the time while providing plasma, providing a magnetic field in or near the plasma, the magnetic field having a position, orientation, and field strength effective to improve the uniformity, density, or both of plasma modification of the surface of the vessel; in which the plasma modification of the surface comprises plasma enhanced chemical vapor deposition (PECVD) and the plasma does not include a substantial amount of hollow cathode plasma.
 2. The method of claim 1, in which the surface is a generally cylindrical interior surface defining at least a portion of a lumen.
 3. The method of claim 1, in which the magnetic field is provided by providing at least one magnetic field generator near the surface, each magnetic field generator having a north pole and a south pole defining a polar axis, in which at least part of the time while providing the magnetic field, at least one magnetic field generator has its polar axis generally parallel to the axis of the surface.
 4. The method of claim 3, in which at least part of the time while providing the magnetic field, at least two magnetic field generators are circumferentially distributed around the surface.
 5. The method of claim 3, in which at least two of the magnetic field generators are rotated about the surface, or the surface rotates with respect to the magnetic field generators, or both, during at least a portion of the plasma treatment.
 6. The method of claim 3, in which at least one magnetic field generator is a permanent magnet.
 7. The method of claim 3, further comprising at least part of the time while providing the magnetic field, translating at least one of the magnetic field generators axially along the surface, or translating the surface with respect to the magnetic field generator, or both, at a rate effective to improve the uniformity of the vessel heating along the axis of the surface.
 8. The method of claim 1, in which the vessel is a vial, a sample tube, a blood tube, a pipe, a catheter, a cuvette, a syringe, or a syringe body and needle assembly, the assembly having a needle end, a back end, and a body portion between the ends.
 9. The method of claim 1, further comprising generating the plasma by providing an outer electrode outside the vessel and an inner electrode at least partially inside the lumen of the vessel and energizing the electrodes using radio frequency energy.
 10. The method of claim 1, in which at least part of the time while providing the magnetic field, at least a portion of the magnetic field in at least a portion of the lumen is oriented with its polar axis extending generally in radial planes with respect to the surface.
 11. The method of claim 1, in which the material supplied to the lumen during at least a portion of the plasma modification comprises: a precursor; optionally an oxidizing gas; and optionally a diluent gas.
 12. The method of claim 11, in which the precursor comprises an organosiloxane, an organo silane, an organosilazane, a hydrocarbon, a fluorinated silane, a fluorocarbon, a parylene, or a combination of two or more of these.
 13. The method of claim 11, in which the precursor comprises an organosiloxane, or organosilazane or organosilane.
 14. The method of claim 13, in which the precursor comprises hexamethyldisiloxane (HMDSO), hexamethyldisilazane, tetramethyldisilazane, octamethylcyclotetrasiloxane (OMCTS), tetrethylorthosilicate (TEOS), trimethylsilane, tetramethylsilane or a combination of these.
 15. The method of claim 11, in which the precursor comprises Parylene N or poly(paraxylylene); Parylene C or poly(2-chloroparaxylylene); Parylene D or poly(2,5-dichloropara-xylylene); Parylene HT® or poly(tetrafluoropara-xylylene), or their dimers, or a combination of two or more of these.
 16. The method of claim 11, in which the precursor comprises dimeric tetrafluoroparaxylylene, difluorocarbene, monomeric tetrafluoroethylene, oligomeric tetrafluoroethylene having the formula F2C═CF(CF2)xF in which x is from 1 to 100, optionally 2 to 50, optionally 2-20, optionally 2-10, sodium chlorodifluoroacetate, chlorodifluoromethane, bromodifluoromethane, hexafluoropropylene oxide, 1 H,1 H,2H,2H-perfluorodecyl acrylate (FDA), a bromofluoroalkane in which the alkane moiety has from 1 to 6 carbon atoms, an iodofluoroalkane in which the alkane moiety has from 1 to 6 carbon atoms, or a combination of any two or more of these.
 17. The method of claim 11, in which the oxidizing gas comprises oxygen, nitrous oxide, water vapor, ozone, hydrogen peroxide or a combination of two or more of these.
 18. The method of claim 11, in which the diluent gas comprises helium, argon, krypton, xenon, neon, nitrogen or a combination of two or more of these.
 19. The method of claim 1, in which the plasma modification comprises application of a barrier coating to the surface of the barrel.
 20. The method of claim 19, in which the barrier coating consists essentially of SiO_(x), in which x is from 1.5 to 2.9.
 21. The method of claim 1, in which the plasma modification comprises application of a pH protective coating to the surface of the barrel, in which the pH protective coating consists essentially of SiOxCy, in which x is from about 0.5 to about 2.4 and y is from about 0.6 to about
 3. 